ES2559230T3 - Heterocyclic Diamino Carboxamide Compound - Google Patents

Heterocyclic Diamino Carboxamide Compound Download PDF

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Publication number
ES2559230T3
ES2559230T3 ES10772177.1T ES10772177T ES2559230T3 ES 2559230 T3 ES2559230 T3 ES 2559230T3 ES 10772177 T ES10772177 T ES 10772177T ES 2559230 T3 ES2559230 T3 ES 2559230T3
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amino
phenyl
carboxamide
methylpiperazin
ethyl
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Itsuro Shimada
Kazuo Kurosawa
Takahiro Matsuya
Kazuhiko Iikubo
Yutaka Kondoh
Akio Kamikawa
Hiroshi Tomiyama
Yoshinori Iwai
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Kotobuki Seiyaku Co Ltd
Astellas Pharma Inc
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Kotobuki Seiyaku Co Ltd
Astellas Pharma Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D241/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms
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    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D241/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms
    • C07D241/28—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms in which said hetero-bound carbon atoms have double bonds to oxygen, sulfur or nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
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    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
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    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/113—Spiro-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring

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  • Engineering & Computer Science (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Macromolecular Compounds Obtained By Forming Nitrogen-Containing Linkages In General (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

Un compuesto de fórmula (I) o una sal del mismo:**Fórmula** (en la que los símbolos son como se definen a continuación: -X-: un grupo de fórmula (II);**Fórmula** A: cloro, etilo o isopropilo; R1: (1) fenilo en el que el carbono en la posición 4 está sustituido con -W-Y-Z y el carbono en la posición 3 puede estar sustituido con un grupo seleccionado del grupo que consiste en halógeno, R00 y -O-R00; Z: un anillo heterocíclico no aromático que puede estar sustituido con uno o más R00; R00: alquilo C1-6 lineal o ramificada que puede estar sustituido con uno o más halógenos; -W-: un enlace, piperidin-1,4-diílo o piperazin-1,4-diílo; -Y-: un enlace; R2: (i) cicloalquilo que puede estar sustituido con uno o más grupos seleccionados del grupo que consiste en N(alquilo C1-6 lineal o ramificado)2, alquilo C1-6 lineal o ramificado, -COO-alquilo C1-6 lineal o ramificado, -OH, -COOH, -CONH-RZB y morfolinilo, o, (ii) un anillo heterocíclico no aromático que puede estar sustituido con uno o más grupos seleccionados del grupo que consiste en alquilo C1-6 lineal o ramificado, -CO-alquilo C1-6 lineal o ramificado, oxo, -CO-RZB y bencilo; RZB: fenilo que puede estar sustituido con un grupo seleccionado del grupo que consiste en halógeno y -O-alquilo C1-6 lineal o ramificado; R3: -H.A compound of formula (I) or a salt thereof: ** Formula ** (in which the symbols are as defined below: -X-: a group of formula (II); ** Formula ** A: chlorine, ethyl or isopropyl; R1: (1) phenyl in which the carbon in position 4 is substituted with -WYZ and the carbon in position 3 may be substituted with a group selected from the group consisting of halogen, R00 and - O-R00; Z: a non-aromatic heterocyclic ring that may be substituted with one or more R00; R00: linear or branched C1-6 alkyl that may be substituted with one or more halogens; -W-: a bond, piperidin-1 , 4-diyl or piperazin-1,4-diyl; -Y-: a bond; R2: (i) cycloalkyl which may be substituted with one or more groups selected from the group consisting of N (linear or branched C1-6 alkyl ) 2, linear or branched C1-6 alkyl, -COO-linear or branched C1-6 alkyl, -OH, -COOH, -CONH-RZB and morpholinyl, or, (ii) a non-aromatic heterocyclic ring that may be substituted with one or more groups selected from the group consisting of linear or branched C1-6 alkyl, -CO-linear or branched C1-6 alkyl, oxo, -CO-RZB and benzyl; RZB: phenyl which may be substituted with a group selected from the group consisting of halogen and linear or branched C1-6 alkyl; R3: -H.

Description

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DESCRIPCIONDESCRIPTION

Compuesto de diamino-carboxamida heterodclica CAMPO TECNICOHeterocyclic Diamino Carboxamide Compound TECHNICAL FIELD

La presente invencion se refiere a compuestos de diamino-carboxamida heterodclica utiles como principios activos en composiciones farmaceuticas, particularmente composiciones farmaceuticas para terapia del cancer.The present invention relates to heterocyclic diaminocarboxamide compounds useful as active ingredients in pharmaceutical compositions, particularly pharmaceutical compositions for cancer therapy.

TECNICA ANTERIORPREVIOUS TECHNIQUE

El cancer de pulmon se produce por el crecimiento desordenado de celulas de la traquea, bronquiales y/o alveolares como resultado de perder sus funciones normales. El numero de personas que mueren de cancer de pulmon es el mayor de las muertes totales por cancer (17 %), y en el mundo aproximadamente 1,3 millones de personas mueren de cancer de pulmon cada ano.Lung cancer is caused by the disorderly growth of trachea, bronchial and / or alveolar cells as a result of losing their normal functions. The number of people who die of lung cancer is the highest of total cancer deaths (17%), and approximately 1.3 million people die of lung cancer each year in the world.

El tratamiento para el cancer de pulmon se divide en tres categonas principales: operacion quirurgica (terapia quirurgica), agente antineoplasico (quimioterapia) e irradiacion radiactiva (radioterapia), pero la eficacia del tratamiento variara dependiendo del tipo de tejido del cancer de pulmon. Por ejemplo, aunque un diagnostico exacto del cancer de pulmon se hace por un patologo basandose en su diagnostico citohistopatologico en un especimen de microscopio, el cancer de pulmon de celulas pequenas, que constituye aproximadamente el 20 % de los casos de cancer de pulmon, frecuentemente ha alcanzado una etapa avanzada en el momento del descubrimiento debido a que generalmente tiene un alto grado de tumor maligno y rapidamente crecera y se diseminara y frecuentemente metastatizara a otros organos. Por este motivo, frecuentemente se usa quimioterapia y/o radioterapia para el tratamiento de este cancer, pero el pronostico es malo debido a que el cancer de pulmon de celulas pequenas frecuentemente volvera a presentarse aunque sea relativamente sensible a estas terapias. Por otra parte, en el caso de cancer de pulmon de celulas no pequenas, que constituye el resto de aproximadamente el 80 %, la terapia quirurgica se considera para su uso hasta una cierta etapa, pero hay poca oportunidad de usar operacion quirurgica en las etapas posteriores en las que la quimioterapia y/o la radioterapia principalmente se usan para el tratamiento.The treatment for lung cancer is divided into three main categories: surgical operation (surgical therapy), antineoplastic agent (chemotherapy) and radioactive irradiation (radiotherapy), but the effectiveness of the treatment will vary depending on the type of lung cancer tissue. For example, although an exact diagnosis of lung cancer is made by a pathologist based on his cytohystopathological diagnosis in a microscope specimen, small cell lung cancer, which constitutes approximately 20% of cases of lung cancer, frequently It has reached an advanced stage at the time of discovery because it generally has a high degree of malignant tumor and will rapidly grow and will spread and frequently metastasize to other organs. For this reason, chemotherapy and / or radiotherapy are often used for the treatment of this cancer, but the prognosis is bad because small cell lung cancer will often come back even if it is relatively sensitive to these therapies. On the other hand, in the case of non-small cell lung cancer, which constitutes the remainder of approximately 80%, surgical therapy is considered for use up to a certain stage, but there is little opportunity to use surgical operation in the stages later in which chemotherapy and / or radiotherapy are mainly used for treatment.

Asf, en cualquier tipo de cancer de pulmon, la quimioterapia es una opcion importante para el tratamiento.Thus, in any type of lung cancer, chemotherapy is an important option for treatment.

La ALK (cinasa de linfoma anaplasico) es una tirosina cinasa de receptor y es una protema que tiene una region transmembranaria en la parte central, flanqueada por una region de tirosina cinasa en el lado del extremo carboxilo y una region extracelular en el lado del extremo amino. Se ha informado previamente de que la ALK de longitud completa se expresa en varios tipos de celulas cancerosas de origen ectodermico (por ejemplo, neuroblastoma, glioblastoma, cancer de mama, melanoma) (Documento no de patente 1). En algunos casos de linfoma maligno humano, tambien se ha informado que el gen ALK esta fusionado con otro gen (por ejemplo, gen NPM, gen CLTCL, gen TFG, gen TPM3, gen ATIC y gen TPM4) como resultado de translocalizacion cromosomica, y asf produce una tirosina cinasa de fusion oncogenica (Science, vol. 263, p. 1281, 1994; Blood, vol. 86, p. 1954, 1995; Blood, vol. 95, p. 3204, 2000; Blood, vol. 94, p. 3265, 1999; Oncogene, vol. 20, p. 5623, 2001). Tambien en el caso de tumor miofibroblastoico inflamatorio se sabe que el gen ALK esta fusionado con otro gen (por ejemplo, gen CARS, gen SEC31L1 y gen RanBP2) como resultado de translocalizacion cromosomica, y asf produce una tirosina cinasa de fusion (Laboratory Investigation, a journal of technical methods and pathology, vol. 83, p. 1255, 2003; International Journal of Cancer, vol. 118, p. 1181, 2006; Medicinal Research Reviews, vol. 28, p. 372, 2008). La mayona de las moleculas componentes que van a fusionarse con ALK tienen un dominio formador de complejo, y los productos de fusion generados tambien parece que ellos mismos forman complejos. Esta formacion de complejos inducina el descontrol de la actividad de tirosina cinasas ALK y la activacion anormal de senales intracelulares, produciendo asf canceracion (Cellular and Molecular Life Science, vol. 61, p. 2939, 2004; Nature Reviews Cancer, vol. 8, p. 11, 2008).ALK (anaplastic lymphoma kinase) is a receptor tyrosine kinase and is a protein that has a transmembrane region in the central part, flanked by a tyrosine kinase region on the side of the carboxyl end and an extracellular region on the side of the end Not me. It has been previously reported that full-length ALK is expressed in several types of cancer cells of ectodermic origin (for example, neuroblastoma, glioblastoma, breast cancer, melanoma) (Non-patent document 1). In some cases of human malignant lymphoma, it has also been reported that the ALK gene is fused with another gene (e.g., NPM gene, CLTCL gene, TFG gene, TPM3 gene, ATIC gene and TPM4 gene) as a result of chromosomal translocation, and thus produces an oncogenic fusion tyrosine kinase (Science, vol. 263, p. 1281, 1994; Blood, vol. 86, p. 1954, 1995; Blood, vol. 95, p. 3204, 2000; Blood, vol. 94 , p. 3265, 1999; Oncogene, vol. 20, p. 5623, 2001). Also in the case of inflammatory myofibroblastoic tumor, it is known that the ALK gene is fused with another gene (for example, CARS gene, SEC31L1 gene and RanBP2 gene) as a result of chromosomal translocation, and thus produces a fusion tyrosine kinase (Laboratory Investigation, a journal of technical methods and pathology, vol. 83, p. 1255, 2003; International Journal of Cancer, vol. 118, p. 1181, 2006; Medicinal Research Reviews, vol. 28, p. 372, 2008). The majority of the component molecules that are to be fused with ALK have a complex-forming domain, and the generated fusion products also appear to form complexes themselves. This complex formation induces the lack of control of ALK tyrosine kinase activity and abnormal activation of intracellular signals, thus causing cancellation (Cellular and Molecular Life Science, vol. 61, p. 2939, 2004; Nature Reviews Cancer, vol. 8, p. 11, 2008).

Ademas, informes recientes han indicado la presencia de una protema de fusion TPM4-ALK en cancer esofagico por procedimientos de analisis de proteomica (World Journal of Gastroenterology, vol. 12, p. 7104, 2006; Journal of Molecular Medicine, vol. 85, p. 863, 2007). Ademas, se confirmo un gen de fusion entre eML4 (4 similar a la protema asociada a los microtubulos de equinodermo) y ALK en espedmenes de pacientes con cancer de pulmon, y tambien se informo que este gen de fusion EML4-ALK tema tumorigenicidad y es un gen causal de cancer, y que inhibidores contra su actividad de cinasa suprimen el crecimiento de diversas celulas en las que se expresa la protema de fusion EML4-ALK (Documento de patente 1 y Documento no de patente 2). Estos documentos muestran adicionalmente que los inhibidores de la protema de fusion EML4-ALK son utiles como agentes terapeuticos para el cancer de pulmon en pacientes con cancer de pulmon positivos para los polinucleotidos EML4-ALK. Ademas, en cancer de pulmon se ha demostrado la presencia de muchas variantes de EML4-ALK (Documento de patente 1; Annals of surgical oncology, vol. 17, p. 889, 2010; Molecular Cancer Research, vol. 7, p. 1466, 2009; Clinical Cancer Research, vol. 15, p. 3143, 2009; Cancer, vol. 115, p. 1723, 2009; Clinical Cancer Research, vol. 14, p. 6618, 2008; Clinical Cancer Research, vol. 14, p. 4275, 2008) y se ha informado de la presencia de TFG-ALK (Cell, vol. 131, p. 1190, 2007) y KIF5B-ALK (Clinical Cancer Research, vol. 15, p. 3143, 2009). Ademas, se sabe que haIn addition, recent reports have indicated the presence of a TPM4-ALK fusion protein in esophageal cancer by proteomic analysis procedures (World Journal of Gastroenterology, vol. 12, p. 7104, 2006; Journal of Molecular Medicine, vol. 85, p. 863, 2007). In addition, a fusion gene between eML4 (4 similar to the protein associated with echinoderm microtubules) and ALK was confirmed in patients with lung cancer, and it was also reported that this EML4-ALK fusion gene is tumorigenic and is a causal cancer gene, and which inhibitors against its kinase activity suppress the growth of various cells in which the EML4-ALK fusion protein is expressed (Patent Document 1 and Non-Patent Document 2). These documents further show that EML4-ALK fusion protein inhibitors are useful as therapeutic agents for lung cancer in patients with lung cancer positive for EML4-ALK polynucleotides. In addition, the presence of many variants of EML4-ALK has been demonstrated in lung cancer (Patent Document 1; Annals of surgical oncology, vol. 17, p. 889, 2010; Molecular Cancer Research, vol. 7, p. 1466 , 2009; Clinical Cancer Research, vol. 15, p. 3143, 2009; Cancer, vol. 115, p. 1723, 2009; Clinical Cancer Research, vol. 14, p. 6618, 2008; Clinical Cancer Research, vol. 14 , p. 4275, 2008) and the presence of TFG-ALK (Cell, vol. 131, p. 1190, 2007) and KIF5B-ALK (Clinical Cancer Research, vol. 15, p. 3143, 2009) has been reported. . In addition, it is known that it has

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habido casos en los que EML4-ALK se expresa en pacientes de cancer de pulmon, ademas de pacientes de cancer de colon y pacientes de cancer de mama (Molecular Cancer Research, vol. 7, p. 1466, 2009).there have been cases in which EML4-ALK is expressed in lung cancer patients, in addition to colon cancer patients and breast cancer patients (Molecular Cancer Research, vol. 7, p. 1466, 2009).

Ademas, el Documento de patente 1 muestra los siguientes compuestos A a D (siendo cada uno conocidos como un inhibidor de ALK) como ejemplos de compuestos que tienen actividad inhibidora contra la protema de fusion EML4- ALK, y tambien desvela los valores reales de sus actividad inhibidora contra la protema de fusion EML4-ALK. Sin embargo, no hay divulgacion espedfica sobre los compuestos de diamino-carboxamida heterodclica segun la presente invencion.In addition, Patent Document 1 shows the following compounds A to D (each being known as an ALK inhibitor) as examples of compounds that have inhibitory activity against EML4-ALK fusion protein, and also discloses the actual values of their inhibitory activity against EML4-ALK fusion protein. However, there is no specific disclosure about the heterocyclic diaminocarboxamide compounds according to the present invention.

imagen1image 1

[Formula 1][Formula 1]

Compuesto ACompound A

H3COH3CO

Compuesto BCompound B

F,GOF, GO

CHCH

Compuesto CCompound C

H3c^s=oH3c ^ s = o

OCHOCH

CHCH

Compuesto DCompound D

H,a. ,.s=oHe has. , .s = o

OCHOCH

Sus nombres qmmicos respectivos son: 4-[(3'-bromo-4'-hidroxifenil)amino]-6,7-dimetoxiquinazolina (tambien llamada WHI-P154) para el compuesto A; N-[2-(3-clorofenil)etil]-2-[(1[4-(trifluorometoxi)fenoxi]acetil}amino)metil]-1,3-tiazol-4- carboxamida para el compuesto B; 5-cloro-N4-[2-(isopropilsulfonil)fenil]-N2-{2-metoxi-4-[4-(4-metilpiperazin-1- il)piperidin-1 -il]fenil}pirimidin-2,4-diamina (tambien llamada TAE684) para el compuesto C; y 2-[(5-bromo-2-{[2- metoxi-4-(4-metilpiperazin-1-il)fenil]amino}pirimidin-4-il)amino]-N-metilbencenosulfonamida para el compuesto D.Their respective chemical names are: 4 - [(3'-bromo-4'-hydroxyphenyl) amino] -6,7-dimethoxyquinazoline (also called WHI-P154) for compound A; N- [2- (3-chlorophenyl) ethyl] -2 - [(1 [4- (trifluoromethoxy) phenoxy] acetyl} amino) methyl] -1,3-thiazol-4- carboxamide for compound B; 5-Chloro-N4- [2- (isopropylsulfonyl) phenyl] -N2- {2-methoxy-4- [4- (4-methylpiperazin-1- yl) piperidin-1-yl] phenyl} pyrimidin-2,4- diamine (also called TAE684) for compound C; and 2 - [(5-bromo-2 - {[2- methoxy-4- (4-methylpiperazin-1-yl) phenyl] amino} pyrimidin-4-yl) amino] -N-methylbenzenesulfonamide for compound D.

Ademas, en las celulas de linfoma que expresan la protema de fusion de ALK, se ha informado que un compuesto que tiene actividad inhibidora de ALK, WHI-P154 (compuesto A mostrado anteriormente), inhibe el crecimiento celular e induce apoptosis (Documento no de patente 3). Sin embargo, no hay divulgacion espedfica sobre los compuestos de diamino-carboxamida heterodclica segun la presente invencion.In addition, in lymphoma cells expressing the ALK fusion protein, it has been reported that a compound that has ALK inhibitory activity, WHI-P154 (compound A shown above), inhibits cell growth and induces apoptosis (Document No. 3) patent. However, there is no specific disclosure about the heterocyclic diaminocarboxamide compounds according to the present invention.

Asimismo, TAE684 (compuesto C mostrado anteriormente) se conoce como un inhibidor de una protema de fusion de un gen de fusion entre el gen NPM y el gen ALK.Also, TAE684 (compound C shown above) is known as an inhibitor of a fusion protein of a fusion gene between the NPM gene and the ALK gene.

TAE684 se diferencia estructuralmente de los compuestos de la presente invencion en que el anillo central intercalado entre dos grupos -NH es un anillo de pirimidina sustituido con cloro.TAE684 differs structurally from the compounds of the present invention in that the central ring interspersed between two -NH groups is a chlorine substituted pyrimidine ring.

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Ademas, se ha informado que TAE684 inhibe la diseminacion de linfoma anaplasico de celulas grandes (ALCL) por su actividad inhibidora contra la protema de fusion NPM-ALK (Documento no de patente 4). Por otra parte, aunque se describe que los compuestos que incluyen TAE684 tienen actividad inhibidora contra la cinasa de adhesion focal (FAK) y asi son utiles para prevenir y/o tratar cancer de pulmon de celulas no pequenas y cancer de pulmon de celulas pequenas, no hay informacion sobre efectos terapeuticos reales sobre estos canceres de pulmon (Documento de patente 2). Ademas, no hay divulgacion espedfica sobre los compuestos de diamino-carboxamida heterodclica segun la presente invencion.In addition, TAE684 has been reported to inhibit the spread of anaplastic large cell lymphoma (ALCL) by its inhibitory activity against the NPM-ALK fusion protein (Non-patent document 4). On the other hand, although it is described that compounds that include TAE684 have inhibitory activity against focal adhesion kinase (FAK) and are thus useful for preventing and / or treating non-small cell lung cancer and small cell lung cancer, There is no information on real therapeutic effects on these lung cancers (Patent Document 2). In addition, there is no specific disclosure about the heterocyclic diaminocarboxamide compounds according to the present invention.

Se concedieron informes adicionales que mostraban que EML4-ALK se expresa en celulas de cancer de pulmon de celulas no pequenas (NCI-H2228), que TFG-ALK se expresa en pacientes con cancer de pulmon de celulas no pequenas y que TAE684 inhibe el crecimiento de celulas de cancer de pulmon de celulas no pequenas (NCI-H2228) (Documento de patente 1 y Documentos no de patente 5 y 6).Additional reports were granted showing that EML4-ALK is expressed in non-small cell lung cancer cells (NCI-H2228), that TFG-ALK is expressed in patients with non-small cell lung cancer and that TAE684 inhibits growth of non-small cell lung cancer cells (NCI-H2228) (Patent document 1 and Non-patent documents 5 and 6).

Ademas, se informa que el siguiente compuesto tiene actividad inhibidora de Syk y es util como principio activo en agentes para prevenir o tratar una enfermedad en la que participa Syk, tal como alergia, inflamacion, enfermedad inmunitaria, trombo y cancer (Documento de patente 3).In addition, the following compound is reported to have Syk inhibitory activity and is useful as an active ingredient in agents to prevent or treat a disease in which Syk participates, such as allergy, inflammation, immune disease, thrombus and cancer (Patent Document 3 ).

imagen2image2

(Para los simbolos en la formula, vease la publicacion.)(For the symbols in the formula, see the publication.)

Sin embargo, no hay divulgacion espedfica sobre los compuestos de diamino-carboxamida heterodclica segun la presente invencion. Ademas, la actividad inhibidora contra la actividad de cinasa de la protema de fusion EML4-ALK ni se ha desvelado ni se ha sugerido, y no hay divulgacion espedfica sobre efectos terapeuticos sobre el cancer.However, there is no specific disclosure about the heterocyclic diaminocarboxamide compounds according to the present invention. In addition, the inhibitory activity against the kinase activity of the EML4-ALK fusion protein has neither been disclosed nor suggested, and there is no specific disclosure of therapeutic effects on cancer.

Ademas, se informa que el siguiente compuesto tiene actividad inhibidora contra la protema cinasa C y es util como principio activo en agentes para prevenir o tratar una enfermedad en la que la protema cinasa C participa, tal como complicacion diabetica, isquemia, inflamacion y cancer (Documento de patente 4).In addition, the following compound is reported to have inhibitory activity against protein kinase C and is useful as an active ingredient in agents to prevent or treat a disease in which protein kinase C participates, such as diabetic complication, ischemia, inflammation and cancer ( Patent document 4).

imagen3image3

(Para los simbolos en la formula, vease la publicacion.)(For the symbols in the formula, see the publication.)

Sin embargo, no hay divulgacion espedfica sobre los compuestos de diamino-carboxamida heterodclica segun la presente invencion. Ademas, la actividad inhibidora contra la actividad de cinasa de la protema de fusion EML4-ALK ni se ha desvelado ni sugerido, y no hay divulgacion espedfica sobre los efectos terapeuticos sobre el cancer.However, there is no specific disclosure about the heterocyclic diaminocarboxamide compounds according to the present invention. In addition, the inhibitory activity against the kinase activity of the EML4-ALK fusion protein has neither been disclosed nor suggested, and there is no specific disclosure about the therapeutic effects on cancer.

Ademas, se informa que el siguiente compuesto tiene actividad inhibidora contra la actividad de cinasa de la protema de fusion EML4-ALK y la protema EGFR mutante y es util como principio activo en agentes terapeuticos para el cancer que incluyen cancer de pulmon, etc. (Documento de patente 5).In addition, the following compound is reported to have an inhibitory activity against the kinase activity of the EML4-ALK fusion protein and the mutant EGFR protein and is useful as an active ingredient in therapeutic agents for cancer that include lung cancer, etc. (Patent document 5).

imagen4image4

(En la formula, -X- es 1,3,5-triazin-2,4-diflo o quinazolin-2,4-diflo que pueden estar sustituidos. Para otros simbolos en la formula, vease la publicacion.)(In the formula, -X- is 1,3,5-triazin-2,4-diflo or quinazolin-2,4-diflo that may be substituted. For other symbols in the formula, see publication.)

Sin embargo, no hay divulgacion espedfica sobre los compuestos de diamino-carboxamida heterodclica segun la 5 presente invencion.However, there is no specific disclosure about the heterocyclic diaminocarboxamide compounds according to the present invention.

Ademas, se informa que el siguiente compuesto tiene actividad inhibidora contra diversas cinasas que incluyen ALK y es util para tratar enfermedad proliferativa de celulas (Documento de patente 6).In addition, the following compound is reported to have inhibitory activity against various kinases that include ALK and is useful for treating cell proliferative disease (Patent Document 6).

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imagen6image6

(Para los simbolos en la formula, vease la publicacion.)(For the symbols in the formula, see the publication.)

Sin embargo, no hay divulgacion espedfica sobre los compuestos de diamino-carboxamida heterodclica segun la presente invencion.However, there is no specific disclosure about the heterocyclic diaminocarboxamide compounds according to the present invention.

Ademas, se informa que el siguiente compuesto tiene actividad inhibidora contra ALK y/o c-Met y es util para tratar enfermedad proliferativa (Documento de patente 7).In addition, the following compound is reported to have inhibitory activity against ALK and / or c-Met and is useful for treating proliferative disease (Patent Document 7).

(Para los simbolos en la formula, vease la publicacion.)(For the symbols in the formula, see the publication.)

Sin embargo, no hay divulgacion espedfica sobre los compuestos de diamino-carboxamida heterodclica segun la 25 presente invencion.However, there is no specific disclosure about the heterocyclic diamino-carboxamide compounds according to the present invention.

Ademas, se informa que el siguiente compuesto tiene actividad inhibidora contra diversas cinasas que incluyen ALK y es util para tratar enfermedad hiperproliferativa y enfermedad angiogenica (Documento de patente 8).In addition, the following compound is reported to have inhibitory activity against various kinases that include ALK and is useful for treating hyperproliferative disease and angiogenic disease (Patent Document 8).

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imagen7image7

(Para los simbolos en la formula, vease la publicacion.)(For the symbols in the formula, see the publication.)

Sin embargo, no hay divulgacion espedfica sobre los compuestos de diamino-carboxamida heterodclica segun la 35 presente invencion.However, there is no specific disclosure about the heterocyclic diaminocarboxamide compounds according to the present invention.

Ademas, se informa que el siguiente compuesto tiene actividad inhibidora contra diversas cinasas que incluyen IGF- 1R y ALK y es util para tratar cancer (Documento de patente 9).In addition, the following compound is reported to have inhibitory activity against various kinases that include IGF-1R and ALK and is useful for treating cancer (Patent Document 9).

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imagen8image8

(Para los s^bolos en la formula, vease la publicacion.)(For the formulas in the formula, see the publication.)

Sin embargo, no hay divulgacion espedfica sobre los compuestos de diamino-carboxamida heterodclica segun la presente invencion.However, there is no specific disclosure about the heterocyclic diaminocarboxamide compounds according to the present invention.

Ademas, se informa que el siguiente compuesto tiene actividad inhibidora de Syk y es util para tratar alergia, enfermedad autoinmunitaria, cancer y crecimiento anormal de celulas mieloides (Documento de patente 10).In addition, the following compound is reported to have Syk inhibitory activity and is useful for treating allergy, autoimmune disease, cancer and abnormal growth of myeloid cells (Patent Document 10).

imagen9image9

(Para los simbolos en la formula, vease la publicacion.)(For the symbols in the formula, see the publication.)

Sin embargo, no hay divulgacion espedfica sobre los compuestos de diamino-carboxamida heterodclica segun la presente invencion. Ademas, la actividad inhibidora contra la actividad de cinasa de la protema de fusion EML4-ALK ni se ha desvelado ni sugerido, y no hay divulgacion espedfica sobre los efectos terapeuticos sobre el cancer.However, there is no specific disclosure about the heterocyclic diaminocarboxamide compounds according to the present invention. In addition, the inhibitory activity against the kinase activity of the EML4-ALK fusion protein has neither been disclosed nor suggested, and there is no specific disclosure about the therapeutic effects on cancer.

Ademas, se informa que el siguiente compuesto tiene actividad inhibidora contra Aurora-B cinasa y es util para tratar cancer, enfermedad infecciosa, inflamacion y enfermedad autoinmunitaria (Documento de patente 11).In addition, the following compound is reported to have inhibitory activity against Aurora-B kinase and is useful for treating cancer, infectious disease, inflammation and autoimmune disease (Patent Document 11).

imagen10image10

(Para los simbolos en la formula, vease la publicacion.)(For the symbols in the formula, see the publication.)

Sin embargo, no hay divulgacion espedfica sobre los compuestos de diamino-carboxamida heterodclica segun la presente invencion. Ademas, la actividad inhibidora contra la actividad de cinasa de la protema de fusion EML4-ALK ni se ha desvelado ni sugerido.However, there is no specific disclosure about the heterocyclic diaminocarboxamide compounds according to the present invention. In addition, the inhibitory activity against the kinase activity of the EML4-ALK fusion protein has neither been disclosed nor suggested.

5 Ademas, se informa que el siguiente compuesto tiene actividad inhibidora de la activacion de STAT6 y actividad inhibidora de la diferenciacion de celulas Th2 y es util para tratar enfermedad respiratoria, asma y enfermedad pulmonar obstructiva cronica (Documento de patente 12).In addition, it is reported that the following compound has inhibitory activity of STAT6 activation and inhibitory activity of Th2 cell differentiation and is useful for treating respiratory disease, asthma and chronic obstructive pulmonary disease (Patent Document 12).

imagen11image11

(Para los simbolos en la formula, vease la publicacion.)(For the symbols in the formula, see the publication.)

Sin embargo, no hay divulgacion espedfica sobre los compuestos de diamino-carboxamida heterodclica segun la presente invencion. Ademas, la actividad inhibidora contra la actividad de cinasa de la protema de fusion EML4-ALK 15 ni se ha desvelado ni sugerido, y no hay divulgacion espedfica sobre los efectos terapeuticos sobre el cancer.However, there is no specific disclosure about the heterocyclic diaminocarboxamide compounds according to the present invention. In addition, the inhibitory activity against the kinase activity of the EML4-ALK 15 fusion protein has neither been disclosed nor suggested, and there is no specific disclosure about the therapeutic effects on cancer.

Ademas, se informa que el siguiente compuesto tiene actividad inhibidora de PKC y es util para tratar alergia, inflamacion, diabetes, cancer y similares (Documento de patente 13).In addition, the following compound is reported to have PKC inhibitory activity and is useful for treating allergy, inflammation, diabetes, cancer and the like (Patent Document 13).

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imagen12image12

(Para los simbolos en la formula, vease la publicacion.)(For the symbols in the formula, see the publication.)

Sin embargo, no hay divulgacion espedfica sobre los compuestos de diamino-carboxamida heterodclica segun la 25 presente invencion. Ademas, la actividad inhibidora contra la actividad de cinasa de la protema de fusion EML4-ALK ni se ha desvelado ni sugerido, y no hay divulgacion espedfica sobre los efectos terapeuticos sobre el cancer.However, there is no specific disclosure about the heterocyclic diamino-carboxamide compounds according to the present invention. In addition, the inhibitory activity against the kinase activity of the EML4-ALK fusion protein has neither been disclosed nor suggested, and there is no specific disclosure about the therapeutic effects on cancer.

Ademas, se informa que el siguiente compuesto tiene actividad inhibidora contra PLK-1 y PLK-3 y es util para tratar cancer, enfermedad proliferativa de celulas, enfermedad por infeccion viral, enfermedad autoinmunitaria y 30 enfermedad neurodegenerativa (Documento de patente 14).In addition, the following compound is reported to have inhibitory activity against PLK-1 and PLK-3 and is useful for treating cancer, proliferative cell disease, viral infection disease, autoimmune disease and neurodegenerative disease (Patent Document 14).

imagen13image13

(Para los simbolos en la formula, vease la publicacion.)(For the symbols in the formula, see the publication.)

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Sin embargo, no hay divulgacion espedfica sobre los compuestos de diamino-carboxamida heterodclica segun la presente invencion. Ademas, la actividad inhibidora contra la actividad de cinasa de la protema de fusion EML4-ALK ni se ha desvelado ni sugerido.However, there is no specific disclosure about the heterocyclic diaminocarboxamide compounds according to the present invention. In addition, the inhibitory activity against the kinase activity of the EML4-ALK fusion protein has neither been disclosed nor suggested.

40 Ademas, se informa que el siguiente compuesto tiene actividad inhibidora de HSP-90 y es util para tratar enfermedad proliferativa de celulas, cancer, inflamacion, artritis y enfermedad angiogenica (Documento de patente 15).In addition, the following compound is reported to have HSP-90 inhibitory activity and is useful for treating proliferative cell disease, cancer, inflammation, arthritis and angiogenic disease (Patent Document 15).

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imagen14image14

(Para los simbolos en la formula, vease la publicacion.)(For the symbols in the formula, see the publication.)

Sin embargo, no hay divulgacion espedfica sobre los compuestos de diamino-carboxamida heterodclica segun la presente invencion. Ademas, la actividad inhibidora contra la actividad de cinasa de la protema de fusion EML4-ALK ni se ha desvelado ni sugerido.However, there is no specific disclosure about the heterocyclic diaminocarboxamide compounds according to the present invention. In addition, the inhibitory activity against the kinase activity of the EML4-ALK fusion protein has neither been disclosed nor suggested.

Ademas, se informa que el siguiente compuesto tiene actividad inhibidora de cinasa ALK, c-Met y Mps1 y es util para tratar enfermedad hiperproliferativa, cancer y enfermedad angiogenica (Documento de patente 16).In addition, the following compound is reported to have ALK, c-Met and Mps1 kinase inhibitory activity and is useful for treating hyperproliferative disease, cancer and angiogenic disease (Patent Document 16).

imagen15image15

(Para los simbolos en la formula, vease la publicacion.)(For the symbols in the formula, see the publication.)

Sin embargo, no hay divulgacion espedfica sobre los compuestos de diamino-carboxamida heterodclica segun la presente invencion.However, there is no specific disclosure about the heterocyclic diaminocarboxamide compounds according to the present invention.

Ademas, se informa que el siguiente compuesto tiene actividad inhibidora contra Syk y Jak y es util para tratar enfermedad cardiaca, inflamacion, enfermedad autoinmunitaria y enfermedad proliferativa de celulas (Documento de patente 17).In addition, the following compound is reported to have inhibitory activity against Syk and Jak and is useful for treating heart disease, inflammation, autoimmune disease and proliferative cell disease (Patent Document 17).

imagen16image16

(Para los simbolos en la formula, vease la publicacion.)(For the symbols in the formula, see the publication.)

Sin embargo, no hay divulgacion espedfica sobre los compuestos de diamino-carboxamida heterodclica segun la presente invencion. Ademas, la actividad inhibidora contra la actividad de cinasa de la protema de fusion EML4-ALK ni se ha desvelado ni sugerido.However, there is no specific disclosure about the heterocyclic diaminocarboxamide compounds according to the present invention. In addition, the inhibitory activity against the kinase activity of the EML4-ALK fusion protein has neither been disclosed nor suggested.

Ademas, se informa que el siguiente compuesto tiene actividad inhibidora de IKK y es util para tratar inflamacion, inmunopatia, cancer, enfermedad neurodegenerativa, enfermedad relacionada con la edad, enfermedad cardiaca y disbolismo (Documento de patente 18).In addition, the following compound is reported to have IKK inhibitory activity and is useful for treating inflammation, immunopathy, cancer, neurodegenerative disease, age-related disease, heart disease and dysbolism (Patent Document 18).

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imagen17image17

(Para los simbolos en la formula, vease la publicacion.)(For the symbols in the formula, see the publication.)

Sin embargo, no hay divulgacion espedfica sobre los compuestos de diamino-carboxamida heterodclica segun la presente invencion. Ademas, la actividad inhibidora contra la actividad de cinasa de la protema de fusion EML4-ALK ni se ha desvelado ni sugerido.However, there is no specific disclosure about the heterocyclic diaminocarboxamide compounds according to the present invention. In addition, the inhibitory activity against the kinase activity of the EML4-ALK fusion protein has neither been disclosed nor suggested.

Ademas, se informa que el siguiente compuesto tiene actividad inhibidora contra diversas cinasas que incluyen ALK y es util para tratar enfermedad proliferativa de celulas y cancer (Documento de patente 19).In addition, the following compound is reported to have inhibitory activity against various kinases that include ALK and is useful for treating cell proliferative disease and cancer (Patent Document 19).

imagen18image18

(Para los simbolos en la formula, vease la publicacion.)(For the symbols in the formula, see the publication.)

Sin embargo, no hay divulgacion espedfica sobre los compuestos de diamino-carboxamida heterodclica segun la presente invencion.However, there is no specific disclosure about the heterocyclic diaminocarboxamide compounds according to the present invention.

Ademas, se informa que el siguiente compuesto tiene actividad inhibidora de cinasa ALK, ROS, IGF-1R e InsR y es util para tratar enfermedad proliferativa de celulas (Documento de patente 20).In addition, the following compound is reported to have ALK, ROS, IGF-1R and InsR kinase inhibitory activity and is useful for treating cell proliferative disease (Patent Document 20).

imagen19image19

(Para los simbolos en la formula, vease la publicacion.)(For the symbols in the formula, see the publication.)

Sin embargo, no hay divulgacion espedfica sobre los compuestos de diamino-carboxamida heterodclica segun la presente invencion.However, there is no specific disclosure about the heterocyclic diaminocarboxamide compounds according to the present invention.

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Ademas, se informa que el siguiente compuesto tiene actividad inhibidora de cinasa ALK, ROS, IGF-1R e InsR y es util para tratar enfermedad proliferativa de celulas (Documento de patente 21).In addition, the following compound is reported to have ALK, ROS, IGF-1R and InsR kinase inhibitory activity and is useful for treating cell proliferative disease (Patent Document 21).

imagen20image20

(Para los simbolos en la formula, vease la publication.)(For the symbols in the formula, see the publication.)

Sin embargo, no hay divulgation espetifica sobre los compuestos de diamino-carboxamida heteroticlica segun la presente invention.However, there is no specific disclosure on heterotic diaminocarboxamide compounds according to the present invention.

LISTA DE CITACIONESLIST OF CITATIONS

DOCUMENTOS DE PATENTEPATENT DOCUMENTS

Documento de Documento de Documento de Documento de Documento de Documento de Documento de Documento de Documento de Documento de Documento de Documento de Documento de Documento de Documento de Documento de Documento de Documento de Documento de Documento de Documento deDocument Document Document Document Document Document Document Document Document Document Document Document Document Document Document Document Document Document Document Document Document Document

patente 1: Publicacion de patente europea N°. EP 1914240 patente 2: Publicacion internacional N°. WO 2004/080980 patente 3: Publicacion internacional N°. WO 00/75113 patente 4: Publicacion internacional N°. WO 00/76980 patente 5: Publicacion internacional N°. WO 2009/008371 patente 6: Publicacion internacional N°. WO 2008/073687 patente 7: Publicacion internacional N°. WO 2008/051547 patente 8: Publicacion internacional N°. WO 2009/032703 patente 9: Publicacion internacional N°. WO 2009/020990 patente 10: Publicacion de patente japonesa N°. 2008-13499 patente 11: Publicacion internacional N°. WO 2008/077885 patente 12: Publicacion internacional N°. WO 2004/002964 patente 13: Publicacion internacional N°. WO 2009/012421 patente 14: Publicacion internacional N°. WO 2009/040399 patente 15: Publicacion internacional N°. WO 2008/024974 patente 16: Publicacion internacional N°. WO 2009/032694 patente 17: Publicacion internacional N°. WO 2009/136995 patente 18: Publicacion internacional N°. WO 2009/089042 patente 19: Publicacion internacional N°. WO 2009/143389 patente 20: Publicacion internacional N°. WO 2009/126514 patente 21: Publicacion internacional N°. WO 2009/126515Patent 1: European Patent Publication No. EP 1914240 Patent 2: International Publication No. WO 2004/080980 Patent 3: International Publication No. WO 00/75113 Patent 4: International Publication No. WO 00/76980 Patent 5: International Publication No. WO 2009/008371 Patent 6: International Publication No. WO 2008/073687 Patent 7: International Publication No. WO 2008/051547 Patent 8: International Publication No. WO 2009/032703 Patent 9: International Publication No. WO 2009/020990 Patent 10: Japanese Patent Publication No. 2008-13499 Patent 11: International Publication No. WO 2008/077885 Patent 12: International Publication No. WO 2004/002964 Patent 13: International Publication No. WO 2009/012421 Patent 14: International Publication No. WO 2009/040399 Patent 15: International Publication No. WO 2008/024974 Patent 16: International Publication No. WO 2009/032694 Patent 17: International Publication No. WO 2009/136995 Patent 18: International Publication No. WO 2009/089042 Patent 19: International Publication No. WO 2009/143389 Patent 20: International Publication No. WO 2009/126514 Patent 21: International Publication No. WO 2009/126515

DOCUMENTOS NO DE PATENTENON-PATENT DOCUMENTS

Documento no de patente 1: International Journal of Cancer, vol. 100, p. 49, 2002 Documento no de patente 2: Nature, vol. 448, no. 2, p. 561,2007Non-patent document 1: International Journal of Cancer, vol. 100, p. 49, 2002 Non-patent document 2: Nature, vol. 448, no. 2 P. 561,2007

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Documento no de patente 3: Laboratory Investigation, vol. 85, p. 1544, 2005Non-patent document 3: Laboratory Investigation, vol. 85, p. 1544, 2005

Documento no de patente 4: Proceedings of the National Academy of Science, vol. 104, no. 1, p. 270, 2007 Documento no de patente 5: Cell, vol. 131, p. 1190, 2007Non-patent document 4: Proceedings of the National Academy of Science, vol. 104, no. 1 p. 270, 2007 Non-patent document 5: Cell, vol. 131, p. 1190, 2007

Documento no de patente 6: Proceedings of the National Academy of Science, vol. 104, no. 50, p. 19936, 2007 RESUMEN DE LA INVENCION PROBLEMAS TECNICOSNon-patent document 6: Proceedings of the National Academy of Science, vol. 104, no. 50, p. 19936, 2007 SUMMARY OF THE INVENTION TECHNICAL PROBLEMS

La presente invencion proporciona un compuesto que es util como principio activo en composiciones farmaceuticas, particularmente composiciones farmaceuticas para la terapia del cancer, y que puede usarse con mas seguridad que un principio activo en composiciones farmaceuticas.The present invention provides a compound that is useful as an active ingredient in pharmaceutical compositions, particularly pharmaceutical compositions for cancer therapy, and which can be used more safely than an active ingredient in pharmaceutical compositions.

SOLUCION A LOS PROBLEMASTROUBLESHOOTING

Como resultado de amplios e intensos estudios sobre compuestos utiles como principios activos en composiciones farmaceuticas para la terapia del cancer, los inventores de la presente invencion han encontrado que el compuesto de diamino-carboxamida heterodclica de la presente invencion tiene excelente actividad inhibidora contra la actividad de cinasa de protemas de fusion EML4-ALK, y es util como principio activo en composiciones farmaceuticas para la terapia del cancer. Este hallazgo condujo a la completitud de la presente invencion.As a result of extensive and intensive studies on useful compounds as active ingredients in pharmaceutical compositions for cancer therapy, the inventors of the present invention have found that the heterocyclic diamino-carboxamide compound of the present invention has excellent inhibitory activity against the activity of EML4-ALK fusion protein kinase, and is useful as an active ingredient in pharmaceutical compositions for cancer therapy. This finding led to the completeness of the present invention.

Concretamente, la presente invencion se refiere a un compuesto de formula (I) o una sal del mismo, ademas de una composicion farmaceutica que comprende un compuesto de formula (I) o una sal del mismo y un excipiente.Specifically, the present invention relates to a compound of formula (I) or a salt thereof, in addition to a pharmaceutical composition comprising a compound of formula (I) or a salt thereof and an excipient.

(I)(I)

(en la que los simbolos son como se definen a continuacion: -X-: un grupo de formula (II)(in which the symbols are as defined below: -X-: a group of formula (II)

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[Formula 21][Formula 21]

R1\ ^ /R2R1 \ ^ / R2

N NN N

H I,H I,

A: cloro, etilo o isopropilo;A: chlorine, ethyl or isopropyl;

R1:R1:

(1) fenilo en el que el carbono en la posicion 4 esta sustituido con -W-Y-Z y el carbono en la posicion 3 puede estar sustituido con un grupo seleccionado del grupo que consiste en halogeno, R00 y -O-R00;(1) phenyl in which the carbon in position 4 is substituted with -W-Y-Z and the carbon in position 3 may be substituted with a group selected from the group consisting of halogen, R00 and -O-R00;

-W-: un enlace, piperidin-1,4-dnlo o piperazin-1,4-diflo;-W-: a bond, piperidin-1,4-dnlo or piperazin-1,4-diflo;

-Y-: un enlace;-Y-: a link;

Z: un anillo heterodclico no aromatico que puede estar sustituido con uno o mas R00;Z: a non-aromatic heterodclic ring that may be substituted with one or more R00;

R2:R2:

(i) cicloalquilo que puede estar sustituido con uno o mas grupos seleccionados del grupo que consiste en - N(alquilo C1-6 lineal o ramificado)2, alquilo C1-6 lineal o ramificado, -COO-alquilo C1-6 lineal o ramificado, - OH, -COOH, -CONH-Rzb y morfolinilo, o(i) cycloalkyl which may be substituted with one or more groups selected from the group consisting of - N (linear or branched C1-6 alkyl) 2, linear or branched C1-6 alkyl, -COO-linear or branched C1-6 alkyl , - OH, -COOH, -CONH-Rzb and morpholinyl, or

(ii) un anillo heterodclico no aromatico que puede estar sustituido con uno o mas grupos seleccionados del grupo que consiste en alquilo Ci-6 lineal o ramificado, -CO-alquilo Ci-6 lineal o ramificado, oxo, -CO-RZB y bencilo;(ii) a non-aromatic heterodclic ring which may be substituted with one or more groups selected from the group consisting of linear or branched Ci-6 alkyl, -CO-linear or branched Ci-6 alkyl, oxo, -CO-RZB and benzyl ;

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Rzb: fenilo que puede estar sustituido con un grupo seleccionado del grupo que consiste en halogeno y -O-alquilo C1- 6 lineal o ramificado;Rzb: phenyl which may be substituted with a group selected from the group consisting of halogen and linear or branched C 1-6 alkyl;

R3: -H.R3: -H.

A menos que se especifique de otro modo, cuando los s^bolos usados en una formula qmmica tambien se usen en otra formula qmmica, los mismos sfmbolos tienen los mismos significados.Unless otherwise specified, when symbols used in a chemical formula are also used in another chemical formula, the same symbols have the same meanings.

La presente invencion tambien se refiere a un inhibidor contra la actividad de cinasa de protema de fusion EML4- ALK, que comprende un compuesto de formula (I) o una sal del mismo.The present invention also relates to an inhibitor against EML4-ALK fusion protein kinase activity, which comprises a compound of formula (I) or a salt thereof.

Ademas, la presente invencion tambien se refiere a una composicion farmaceutica para la terapia del cancer, que comprende un compuesto de formula (I) o una sal del mismo. Debe observarse que la composicion farmaceutica incluye un agente terapeutico para el cancer, que comprende un compuesto de formula (I) o una sal del mismo.In addition, the present invention also relates to a pharmaceutical composition for cancer therapy, which comprises a compound of formula (I) or a salt thereof. It should be noted that the pharmaceutical composition includes a therapeutic agent for cancer, which comprises a compound of formula (I) or a salt thereof.

Ademas, la presente invencion tambien se refiere a una composicion farmaceutica que comprende un compuesto de formula (1) o una sal del mismo y un excipiente farmaceutico; una composicion farmaceutica para su uso en un metodo de prevencion y tratamiento de cancer, cancer de pulmon, cancer de pulmon no pequeno, cancer de pulmon de celulas pequenas, cancer positivo para los polinucleotidos de fusion EML4-ALK, cancer de pulmon positivo para los polinucleotidos de fusion EML4-ALK, o cancer de pulmon no pequeno positivo para los polinucleotidos de fusion EML4-ALK, que comprende un compuesto de formula (I) o una sal del mismo, un compuesto de formula (1) o una sal del mismo para su uso en un metodo como inhibidor contra la actividad de cinasa de la protema de fusion EML4- ALK; un compuesto de formula (I) o una sal del mismo para su uso en un metodo para la prevencion y tratamiento de cancer.In addition, the present invention also relates to a pharmaceutical composition comprising a compound of formula (1) or a salt thereof and a pharmaceutical excipient; a pharmaceutical composition for use in a method of prevention and treatment of cancer, lung cancer, non-small lung cancer, small cell lung cancer, EML4-ALK fusion polynucleotide positive cancer, lung positive cancer EML4-ALK fusion polynucleotides, or non-small lung cancer positive for EML4-ALK fusion polynucleotides, comprising a compound of formula (I) or a salt thereof, a compound of formula (1) or a salt thereof for use in a method as an inhibitor against the kinase activity of the EML4-ALK fusion protein; a compound of formula (I) or a salt thereof for use in a method for the prevention and treatment of cancer.

EFECTO VENTAJOSO DE LA INVENCIONADVANTAGE EFFECT OF THE INVENTION

El compuesto de formula (I) o una sal del mismo tiene actividad inhibidora contra la actividad de cinasa de la protema de fusion EML4-ALK, ademas de la actividad inhibidora del crecimiento contra celulas dependientes de la protema de fusion EML4-ALK, y puede usarse como principio activo en composiciones farmaceuticas para prevenir y/o tratar cancer, tal como cancer de pulmon en una realizacion, cancer de pulmon de celulas no pequenas o cancer de pulmon de celulas pequenas en otra realizacion, cancer positivo para los polinucleotidos de fusion ALK en otra realizacion mas, cancer de pulmon positivo para los polinucleotidos de fusion ALK en otra realizacion mas, cancer de pulmon de celulas no pequenas positivo para los polinucleotidos de fusion ALK en otra realizacion mas, cancer positivo para la protema de fusion de ALK en otra realizacion mas, cancer de pulmon positivo para la protema de fusion de ALK en otra realizacion mas, cancer de pulmon de celulas no pequenas positivo para la protema de fusion de ALK en otra realizacion mas, cancer positivo para los polinucleotidos de fusion EML4-ALK en otra realizacion mas, cancer de pulmon positivo para los polinucleotidos de fusion EML4-ALK en otra realizacion mas, cancer de pulmon de celulas no pequenas positivo para los polinucleotidos de fusion EML4-ALK en otra realizacion mas, cancer positivo para la protema de fusion EML4-ALK en otra realizacion mas, cancer de pulmon positivo para la protema de fusion EML4-ALK en otra realizacion mas, o cancer de pulmon de celulas no pequenas positivo para la protema de fusion EML4-ALK en otra realizacion mas.The compound of formula (I) or a salt thereof has inhibitory activity against the kinase activity of the EML4-ALK fusion protein, in addition to the growth inhibitory activity against cells dependent on the EML4-ALK fusion protein, and can used as an active ingredient in pharmaceutical compositions for preventing and / or treating cancer, such as lung cancer in one embodiment, non-small cell lung cancer or small cell lung cancer in another embodiment, positive cancer for ALK fusion polynucleotides in another embodiment, lung cancer positive for ALK fusion polynucleotides in another embodiment, non-small cell lung cancer positive for ALK fusion polynucleotides in another embodiment, positive cancer for ALK fusion protein in another further embodiment, lung cancer positive for the fusion protein of ALK in yet another embodiment, non-small cell lung cancer positive for the prot Ema fusion of ALK in yet another embodiment, positive cancer for EML4-ALK fusion polynucleotides in yet another embodiment, positive lung cancer for EML4-ALK fusion polynucleotides in yet another embodiment, non-small cell lung cancer positive for EML4-ALK fusion polynucleotides in yet another embodiment, cancer positive for EML4-ALK fusion protein in yet another embodiment, lung cancer positive for EML4-ALK fusion protein in yet another embodiment, or lung cancer Non-small cells positive for EML4-ALK fusion protein in yet another embodiment.

DESCRIPCION DE REALIZACIONESDESCRIPTION OF EMBODIMENTS

La presente invencion se describira ahora mas abajo en mas detalle.The present invention will now be described below in more detail.

Como se usa en el presente documento, el termino “halogeno” significa F, Cl, Br o I.As used herein, the term "halogen" means F, Cl, Br or I.

El termino “alquilo inferior” se refiere a alquilo lineal o ramificado que contiene 1 a 6 atomos de carbono (en lo sucesivo abreviado como “CW). Ejemplos incluyen metilo, etilo, n-propilo, isopropilo, n-butilo, isobutilo, sec-butilo, terc-butilo, n-pentilo, n-hexilo y similares. Otra realizacion es alquilo C1-4, y otra realizacion mas es metilo, etilo o isopropilo.The term "lower alkyl" refers to linear or branched alkyl containing 1 to 6 carbon atoms (hereinafter abbreviated as "CW). Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl and the like. Another embodiment is C1-4 alkyl, and another embodiment is methyl, ethyl or isopropyl.

El termino “alquenilo inferior” se refiere a un grupo monovalente de una cadena de hidrocarburo C2-6 lineal o ramificada que tiene al menos un doble enlace. Ejemplos incluyen vinilo, propenilo, isopropenilo, butenilo, pentenilo, 1 -metilvinilo, 1-metil-2-propenilo, 1,3-butadienilo, 1,3-pentadienilo, etc. Otra realizacion es isopropenilo.The term "lower alkenyl" refers to a monovalent group of a linear or branched C2-6 hydrocarbon chain having at least one double bond. Examples include vinyl, propenyl, isopropenyl, butenyl, pentenyl, 1-methylvinyl, 1-methyl-2-propenyl, 1,3-butadienyl, 1,3-pentadienyl, etc. Another embodiment is isopropenyl.

El termino “cicloalquilo” se refiere a un grupo de hidrocarburo dclico saturado C3-10 opcionalmente conectado, que incluye ciclopropilo, ciclobutilo, ciclopentilo, ciclohexilo, cicloheptilo, ciclooctilo, biciclo[2.2.1]heptilo, biciclo[3.1.1]heptilo, adamantilo, etc. Otros ejemplos incluyen aquellos parcialmente insaturados, tal como ciclopentenilo, ciclohexenilo, ciclooctadienilo, biciclo[3.1.1]heptenilo, etc.The term "cycloalkyl" refers to an optionally connected C3-10 saturated hydrocarbon group which includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, bicyclo [3.1.1] heptyl, adamantyl, etc. Other examples include those partially unsaturated, such as cyclopentenyl, cyclohexenyl, cyclooctadienyl, bicyclo [3.1.1] heptenyl, etc.

El termino “amino dclico” se refiere a un grupo monovalente de una amina dclica no aromatica monodclica de 3 a 8 miembros que tiene al menos un atomo de nitrogeno y adicionalmente puede tener uno o mas heteroatomos iguales o diferentes seleccionados del grupo que consiste en nitrogeno, oxfgeno y azufre, en el que al menos un atomo deThe term "dyl amino" refers to a monovalent group of a 3 to 8 membered mono-aromatic non-aromatic cyclic amine that has at least one nitrogen atom and can additionally have one or more same or different heteroatoms selected from the group consisting of nitrogen , oxygen and sulfur, in which at least one atom of

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nitrogeno tiene una mano de union. Ejemplos espedficos incluyen aziridinilo, azetidinilo, pirrolidinilo, piperidinilo, azepanilo, azocanilo, piperazinilo, homopiperazinilo, morfolinilo, oxazepanilo, tiomorfolinilo, tiazepanilo y similares. Alternativamente, otra realizacion es un grupo monovalente de una amina dclica no aromatica monodclica que 5 o 6 miembros. Otra realizacion mas es pirrolidinilo, piperidinilo, piperazinilo o morfolinilo. Debe observarse que un anillo tal puede estar conectado, como se ejemplifica por 2,5-diazabiciclo[2.2.1]heptilo, 9-azabiciclo[3.3.1]nonilo y similares, o puede tener un enlace insaturado en parte del anillo, como se ejemplifica por dihidropirrolilo, dihidropiridilo, tetrahidropiridilo, tetrahidropirazilo o similares.Nitrogen has a bonding hand. Specific examples include aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, azocanyl, piperazinyl, homopiperazinyl, morpholinyl, oxazepanyl, thiomorpholinyl, thiazepanyl and the like. Alternatively, another embodiment is a monovalent group of a monocyclic non-aromatic cyclic amine having 5 or 6 members. Another embodiment is pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl. It should be noted that such a ring may be connected, as exemplified by 2,5-diazabicyclo [2.2.1] heptyl, 9-azabicyclo [3.3.1] nonyl and the like, or it may have an unsaturated bond in part of the ring, such as it is exemplified by dihydropyrrolyl, dihydropyridyl, tetrahydropyridyl, tetrahydropyrazyl or the like.

El termino “anillo heterodclico no aromatico” se refiere a un grupo monovalente de un anillo heterodclico monodclico no aromatico de 3 a 10 miembros que tiene 1 a 4 heteroatomos seleccionados del grupo que consiste en nitrogeno, oxigeno y azufre. Ejemplos incluyen aziridinilo, azetidinilo, pirrolidinilo, piperidinilo, azepanilo, diazepanilo, azocanilo, piperazinilo, homopiperazinilo, morfolinilo, oxazepanilo, tiomorfolinilo, tiazepanilo, tetrahidropiranilo, tetrahidrofurilo, dioxanilo, dioxolanilo, tetrahidrotienilo, tetrahidrotiopiranilo y similares. Otra realizacion es un grupo monovalente de un anillo heterodclico no aromatico monodclico de 5 o 6 miembros. Debe observarse que un anillo tal puede estar conectado, como se ejemplifica por 2,5-diazabiciclo[2.2.1]heptilo, 9- azabiciclo[3.3.1]nonilo o similares, o puede tener un enlace insaturado en parte del anillo, como se ejemplifica por dihidropirrolilo, dihidropiridilo, tetrahidropiridilo, tetrahidropirazilo o similares.The term "non-aromatic heterodclic ring" refers to a monovalent group of a 3 to 10-membered non-aromatic monodyl heterodyl ring having 1 to 4 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. Examples include aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, diazepanyl, azocanyl, piperazinyl, homopiperazinyl, morpholinyl, oxazepanyl, thiomorpholinyl, thiazepanyl, tetrahydropyranyl, tetrahydrofuryl, dioxanyl, dioxolanyl, tetrahydrothienyl, tetrahydrothiopyranyl and the like. Another embodiment is a monovalent group of a 5- or 6-membered monodyl non-aromatic heterodyl ring. It should be noted that such a ring may be connected, as exemplified by 2,5-diazabicyclo [2.2.1] heptyl, 9-azabicyclo [3.3.1] nonyl or the like, or it may have an unsaturated bond in part of the ring, such as it is exemplified by dihydropyrrolyl, dihydropyridyl, tetrahydropyridyl, tetrahydropyrazyl or the like.

El termino “anillo heterodclico aromatico” se refiere a un grupo monovalente de un anillo heterodclico aromatico monodclico de 5 a 10 miembros que tiene 1 a 4 heteroatomos seleccionados del grupo que consiste en nitrogeno, oxigeno y azufre. Ejemplos incluyen piridilo, pirrolilo, pirazinilo, pirimidinilo, piridazinilo, imidazolilo, pirazolilo, tiazolilo, oxazolilo, tienilo, furilo, 1,2,4-oxadiazolilo y similares. Otra realizacion es piridilo, imidazolilo o pirazolilo. Otra realizacion mas es piridilo.The term "aromatic heterodclic ring" refers to a monovalent group of a 5-10 membered monodyl aromatic heterodyl ring having 1 to 4 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. Examples include pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, thienyl, furyl, 1,2,4-oxadiazolyl and the like. Another embodiment is pyridyl, imidazolyl or pyrazolyl. Another embodiment is pyridyl.

El termino “polinucleotido de fusion ALK” se refiere a un polinucleotido de fusion en el que el gen ALK esta fusionado con otro gen y asi expresa una tirosina cinasa de fusion oncogenica. Ejemplos incluyen el polinucleotido de fusion EML4-ALK, polinucleotido de fusion TFG-ALK, polinucleotido de fusion KIF5-ALK, polinucleotido de fusion NPM- ALK, polinucleotido de fusion CLTCL-ALK, polinucleotido de fusion TPM3-ALK, polinucleotido de fusion TPM4-ALK, polinucleotido de fusion ATIC-ALK, polinucleotido de fusion CARS-ALK, polinucleotido de fusion SEC31L1-ALK, polinucleotido de fusion RanBP2-ALKy similares.The term "ALK fusion polynucleotide" refers to a fusion polynucleotide in which the ALK gene is fused with another gene and thus expresses an oncogenic fusion tyrosine kinase. Examples include the EML4-ALK fusion polynucleotide, TFG-ALK fusion polynucleotide, KIF5-ALK fusion polynucleotide, NPM-ALK fusion polynucleotide, CLTCL-ALK fusion polynucleotide, TPM3-ALK fusion polynucleotide, TPM4- fusion polynucleotide. ALK, ATIC-ALK fusion polynucleotide, CARS-ALK fusion polynucleotide, SEC31L1-ALK fusion polynucleotide, similar RanBP2-ALK fusion polynucleotide.

El termino “protema de fusion de ALK” se refiere a una tirosina cinasa de fusion producida por la expresion del polinucleotido de fusion ALK.The term "ALK fusion protein" refers to a fusion tyrosine kinase produced by the expression of the ALK fusion polynucleotide.

El termino “polinucleotido de fusion EML4-ALK” se refiere a un polinucleotido de fusion en el que el gen ALK esta fusionado con el gen EML4 y asi expresa una protema de fusion de ALK oncogenica, que incluye variantes de la misma, tal como el polinucleotido de fusion EML4-ALK v1 (polinucleotido de SEC ID N°: 1 del Documento de patente 1), el polinucleotido de fusion EML4-ALK v2 (polinucleotido de SEC ID N°: 6 del Documento de patente 1) y el polinucleotido de fusion EML4-ALK v3 (polinucleotido de SEC ID N°: 129 del Documento de patente 1), ademas de diversas variantes (Annals of surgical oncology, vol. 17, p. 889, 2010, Molecular Cancer Research, vol. 7, p. 1466, 2009, Clinical Cancer Research, vol. 15, p. 3143, 2009, Cancer, vol. 115, p. 1723, 2009, Clinical Cancer Research, vol. 14, p. 6618, 2008, Clinical Cancer Research, vol. 14, p. 4275, 2008, etc.).The term "EML4-ALK fusion polynucleotide" refers to a fusion polynucleotide in which the ALK gene is fused with the EML4 gene and thus expresses an oncogenic ALK fusion protein, which includes variants thereof, such as the EML4-ALK v1 fusion polynucleotide (polynucleotide of SEQ ID No. 1 of Patent Document 1), EML4-ALK v2 fusion polynucleotide (polynucleotide of SEQ ID No. 6 of Patent Document 1) and the polynucleotide of EML4-ALK v3 fusion (polynucleotide of SEQ ID NO: 129 of Patent Document 1), in addition to various variants (Annals of surgical oncology, vol. 17, p. 889, 2010, Molecular Cancer Research, vol. 7, p . 1466, 2009, Clinical Cancer Research, vol. 15, p. 3143, 2009, Cancer, vol. 115, p. 1723, 2009, Clinical Cancer Research, vol. 14, p. 6618, 2008, Clinical Cancer Research, vol .14, p. 4275, 2008, etc.).

El termino “protema de fusion EML4-ALK” se refiere a una tirosina cinasa de fusion creada por la expresion del polinucleotido de fusion EML4-ALK.The term "EML4-ALK fusion protein" refers to a fusion tyrosine kinase created by the expression of the EML4-ALK fusion polynucleotide.

Un compuesto de formula (I) o una sal del mismo en la que -X- en la formula (I) representa un grupo de formula (II) significa un compuesto de formula (V) o una sal del mismo.A compound of formula (I) or a salt thereof in which -X- in formula (I) represents a group of formula (II) means a compound of formula (V) or a salt thereof.

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La expresion “puede estar sustituido” pretende significar “sin sustituir” o “que tiene 1 a 5 sustituyentes”. Cuando estan sustituidos con una pluralidad de grupos, estos grupos pueden ser iguales o diferentes entre si.The expression "may be substituted" is intended to mean "unsubstituted" or "having 1 to 5 substituents." When substituted with a plurality of groups, these groups may be the same or different from each other.

La expresion “esta (estan) sustituido(s)” o “sustituido(s)” pretende significar “que tiene 1 a 5 sustituyentes”. Cuando estan sustituidos con una pluralidad de grupos, estos grupos pueden ser iguales o diferentes entre si.The expression "is (are) substituted" or "substituted (s)" is intended to mean "having 1 to 5 substituents". When substituted with a plurality of groups, these groups may be the same or different from each other.

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La expresion “alquilo inferior que puede estar sustituido con uno o mas halogenos” se refiere a, por ejemplo, alquilo inferior que puede estar sustituido con 1 a 7 halogenos iguales o diferentes. Otra realizacion es alquilo inferior que puede estar sustituido con 1 a 5 halogenos. Otra realizacion mas es alquilo inferior que puede estar sustituido con 1 a 3 halogenos.The term "lower alkyl which may be substituted with one or more halogens" refers to, for example, lower alkyl which may be substituted with 1 to 7 identical or different halogens. Another embodiment is lower alkyl which may be substituted with 1 to 5 halogens. Another embodiment is lower alkyl which may be substituted with 1 to 3 halogens.

La expresion “alquenilo inferior que puede estar sustituido con uno o mas halogenos” se refiere a, por ejemplo, alquenilo inferior que puede estar sustituido con 1 a 3 halogenos.The term "lower alkenyl which may be substituted with one or more halogens" refers to, for example, lower alkenyl which may be substituted with 1 to 3 halogens.

Algunas realizaciones de los compuestos de formula (I) o una sal de los mismos, se dan a continuacion.Some embodiments of the compounds of formula (I) or a salt thereof, are given below.

(1) Compuestos de formula (I) o una sal de los mismos, en los que(1) Compounds of formula (I) or a salt thereof, in which

(1-4) -X- es un grupo de formula (II), y A es cloro, etilo o isopropilo,(1-4) -X- is a group of formula (II), and A is chlorine, ethyl or isopropyl,

(1-5) -X- es un grupo de formula (II), y A es cloro,(1-5) -X- is a group of formula (II), and A is chlorine,

(1-6) -X- es un grupo de formula (II), y A es etilo o isopropilo,(1-6) -X- is a group of formula (II), and A is ethyl or isopropyl,

(1-7) -X- es un grupo de formula (II), y A es etilo, o(1-7) -X- is a group of formula (II), and A is ethyl, or

(1-8) -X- es un grupo de formula (II), y A es isopropilo.(1-8) -X- is a group of formula (II), and A is isopropyl.

(2) Compuestos de formula (I) o una sal de los mismos, en los que(2) Compounds of formula (I) or a salt thereof, in which

(2-2) R1 es fenilo en el que el carbono en la posicion 4 esta sustituido con -W-Y-Z y el carbono en la posicion 3 puede estar sustituido con un grupo seleccionado del grupo que consiste en halogeno, R00, y -O- R00, R00 es alquilo inferior que puede estar sustituido con uno o mas halogenos, -Y- es un enlace y Z es un anillo heterodclico no aromatico que puede estar sustituido con uno o mas R00,(2-2) R1 is phenyl in which the carbon in position 4 is substituted with -WYZ and the carbon in position 3 may be substituted with a group selected from the group consisting of halogen, R00, and -O- R00 , R00 is lower alkyl which may be substituted with one or more halogens, -Y- is a bond and Z is a non-aromatic heterodyl ring that may be substituted with one or more R00,

(2-3) R1 es fenilo en el que el carbono en la posicion 4 esta sustituido con un grupo seleccionado del grupo que consiste en 4-(4-metilpiperazin-1-il)piperidin-1-ilo, 4-(1-metilpiperidin-4-il)piperazin-1-ilo, 4-metilpiperazin-1-ilo y 4- isopropilpiperazin-1-ilo y el carbono en la posicion 3 puede estar sustituido con un grupo seleccionado del grupo que consiste en fluor, metilo, trifluorometilo y metoxi,(2-3) R1 is phenyl in which the carbon in position 4 is substituted with a group selected from the group consisting of 4- (4-methylpiperazin-1-yl) piperidin-1-yl, 4- (1- methylpiperidin-4-yl) piperazin-1-yl, 4-methylpiperazin-1-yl and 4- isopropylpiperazin-1-yl and carbon at position 3 may be substituted with a group selected from the group consisting of fluorine, methyl, trifluoromethyl and methoxy,

(2-4) R1 es fenilo en el que el carbono en la posicion 4 esta sustituido con 4-(4-metilpiperazin-1-il)piperidin-1-ilo y el carbono en la posicion 3 puede estar sustituido con un grupo seleccionado del grupo que consiste en metilo, trifluorometilo y metoxi,(2-4) R1 is phenyl in which the carbon in position 4 is substituted with 4- (4-methylpiperazin-1-yl) piperidin-1-yl and the carbon in position 3 can be substituted with a selected group from the group consisting of methyl, trifluoromethyl and methoxy,

(2-5) R es fenilo en el que el carbono en la posicion 4 esta sustituido con 4-metilpiperazin-1-ilo y el carbono en la posicion 3 puede estar sustituido con un grupo seleccionado del grupo que consiste en fluor y metoxi,(2-5) R is phenyl in which the carbon in position 4 is substituted with 4-methylpiperazin-1-yl and the carbon in position 3 may be substituted with a group selected from the group consisting of fluorine and methoxy,

(2-6) R1 es 4-{4-(4-metilpiperazin-1-il)piperidin-1-il}fenilo,(2-6) R1 is 4- {4- (4-methylpiperazin-1-yl) piperidin-1-yl} phenyl,

(2-7) R1 es 3-metil-4-{4-(4-metilpiperazin-1-il)piperidin-1-il}fenilo,(2-7) R1 is 3-methyl-4- {4- (4-methylpiperazin-1-yl) piperidin-1-yl} phenyl,

(2-8) R1 es 4-{4-(4-metilpiperazin-1-il)piperidin-1-il}-3-(trifluorometil)fenilo,(2-8) R1 is 4- {4- (4-methylpiperazin-1-yl) piperidin-1-yl} -3- (trifluoromethyl) phenyl,

(2-9) R1 es 3-metoxi-4-{4-(4-metilpiperazin-1-il)piperidin-1-il}fenilo,(2-9) R1 is 3-methoxy-4- {4- (4-methylpiperazin-1-yl) piperidin-1-yl} phenyl,

(2-10) R1 es 4-(4-metilpiperazin-1-il)fenilo,(2-10) R1 is 4- (4-methylpiperazin-1-yl) phenyl,

(2-11) R1 es 3-fluoro-4-(4-metilpiperazin-1-il)fenilo,(2-11) R1 is 3-fluoro-4- (4-methylpiperazin-1-yl) phenyl,

(2-12) R1 es 3-metoxi-4-(4-metilpiperazin-1-il)fenilo,(2-12) R1 is 3-methoxy-4- (4-methylpiperazin-1-yl) phenyl,

(2-13) R1 es 3-metil-4-{4-(1-metilpiperidin-4-il)piperazin-1-il}fenilo, o (2-14) R1 es 4-(4-isopropilpiperazin-1-il)-3-metilfenilo.(2-13) R1 is 3-methyl-4- {4- (1-methylpiperidin-4-yl) piperazin-1-yl} phenyl, or (2-14) R1 is 4- (4-isopropylpiperazin-1- il) -3-methylphenyl.

(3) Compuestos de formula (I) o una sal de los mismos, en la que (3-1) R2 es(3) Compounds of formula (I) or a salt thereof, in which (3-1) R2 is

(i) cicloalquilo que puede estar sustituido con uno o mas grupos seleccionados del grupo que consiste en -N(alquilo inferior^, alquilo inferior, -COO-alquilo inferior, -OH, -COOH, -CONH-RZB y morfolinilo, o(i) cycloalkyl which may be substituted with one or more groups selected from the group consisting of -N (lower alkyl ^, lower alkyl, -COO-lower alkyl, -OH, -COOH, -CONH-RZB and morpholinyl, or

(ii) un anillo heterodclico no aromatico que puede estar sustituido con uno o mas grupos seleccionados del grupo que consiste en alquilo inferior, -CO-alquilo inferior, oxo, -CO-RZb y bencilo,(ii) a non-aromatic heterodyl ring which may be substituted with one or more groups selected from the group consisting of lower alkyl, -CO-lower alkyl, oxo, -CO-RZb and benzyl,

(3-2) R2 es cicloalquilo que puede estar sustituido con uno o mas grupos seleccionados del grupo que consiste en -N(alquilo inferior^, alquilo inferior, -COO-alquilo inferior, -OH, -COOh, -CONH-RZBy morfolinilo,(3-2) R2 is cycloalkyl which may be substituted with one or more groups selected from the group consisting of -N (lower alkyl ^, lower alkyl, -COO-lower alkyl, -OH, -COOh, -CONH-RZB and morpholinyl ,

(3-3) R2 es un anillo heterodclico no aromatico que puede estar sustituido con uno o mas grupos seleccionados del grupo que consiste en alquilo inferior, -CO-alquilo inferior, oxo, -CO-RZB y bencilo,(3-3) R2 is a non-aromatic heterodclic ring that may be substituted with one or more groups selected from the group consisting of lower alkyl, -CO-lower alkyl, oxo, -CO-RZB and benzyl,

(3-4) R2 es(3-4) R2 is

(i) ciclohexilo que puede estar sustituido con uno o mas grupos seleccionados del grupo que consiste en -N(alquilo inferior^, alquilo inferior, -COO-alquilo inferior, -OH, -COOH, -CONH-RZB y morfolinilo,(i) cyclohexyl which may be substituted with one or more groups selected from the group consisting of -N (lower alkyl ^, lower alkyl, -COO-lower alkyl, -OH, -COOH, -CONH-RZB and morpholinyl,

(ii) piperidinilo que puede estar sustituido con uno o mas grupos seleccionados del grupo que consiste en alquilo inferior, -CO-alquilo inferior, oxo, -CO-RZB y bencilo, o(ii) piperidinyl which may be substituted with one or more groups selected from the group consisting of lower alkyl, -CO-lower alkyl, oxo, -CO-RZB and benzyl, or

(iii) tetrahidropiranilo,(iii) tetrahydropyranyl,

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(3-5) R2 es ciclohexilo que puede estar sustituido con uno o mas grupos seleccionados del grupo que consiste en -N(alquilo inferior)2, alquilo inferior, -COO-alquilo inferior, -OH, - COOH, -CONH-RZB y morfolinilo,(3-5) R2 is cyclohexyl which may be substituted with one or more groups selected from the group consisting of -N (lower alkyl) 2, lower alkyl, -COO-lower alkyl, -OH, - COOH, -CONH-RZB and morpholinyl,

(3-6) R2 es piperidinilo que puede estar sustituido con uno o mas grupos seleccionados del grupo que consiste en alquilo inferior, -CO-alquilo inferior, oxo, -CO-RZB y bencilo,(3-6) R2 is piperidinyl which may be substituted with one or more groups selected from the group consisting of lower alkyl, -CO-lower alkyl, oxo, -CO-RZB and benzyl,

(3-7) R2 es tetrahidropiranilo,(3-7) R2 is tetrahydropyranyl,

(3-8) R2 es 4-hidroxiciclohexilo, 4-hidroxi-4-metilciclohexilo o tetrahidropiran-4-ilo,(3-8) R2 is 4-hydroxycyclohexyl, 4-hydroxy-4-methylcyclohexyl or tetrahydropyran-4-yl,

(3-9) R2 es 4-hidroxiciclohexilo,(3-9) R2 is 4-hydroxycyclohexyl,

(3-10) R2 es 4-hidroxi-4-metilciclohexilo, o (3-11) R2 es tetrahidropiran-4-ilo.(3-10) R2 is 4-hydroxy-4-methylcyclohexyl, or (3-11) R2 is tetrahydropyran-4-yl.

(4) Compuestos de formula (I) o una sal de los mismos, en la que R3 es -H.(4) Compounds of formula (I) or a salt thereof, wherein R3 is -H.

(5) Compuestos, en los que se aplica cualquier combinacion de dos o mas de (1) a (4) mostrados anteriormente. Ejemplos de realizaciones de la combinacion incluyen:(5) Compounds, in which any combination of two or more of (1) to (4) shown above applies. Examples of embodiments of the combination include:

(5-1) Compuestos o una sal de los mismos, en los que se aplican (1) y (4) mostrados anteriormente,(5-1) Compounds or a salt thereof, in which (1) and (4) shown above apply,

(5-2) Compuestos o una sal de los mismos, en los que se aplican (1), (2) y (4) mostrados anteriormente,(5-2) Compounds or a salt thereof, in which (1), (2) and (4) shown above apply,

(5-3) Compuestos o una sal de  (5-3) Compounds or a salt of
los mismos, en los que se aplican (1), (2), (3) y (4) mostrados anteriormente,  the same, in which they apply (1), (2), (3) and (4) shown above,

(5-6) Compuestos anteriormente,  (5-6) Compounds above,
o una sal de los mismos, en los que se aplican (1-4), (2-2), (3-1) y (4) mostrados  or a salt thereof, in which they are applied (1-4), (2-2), (3-1) and (4) shown

(5-7) Compuestos anteriormente,  (5-7) Compounds above,
o una sal de los mismos, en los que se aplican (1-4), (2-3), (3-1) y (4) mostrados  or a salt thereof, in which they are applied (1-4), (2-3), (3-1) and (4) shown

(5-8) Compuestos  (5-8) Compounds
o una sal de los mismos, en los que se aplican (1-4), (2-3), (3-8) y (4) mostrados  or a salt thereof, in which they are applied (1-4), (2-3), (3-8) and (4) shown

anteriormente, yabove, and

(5-9) Compuestos o una sal de los mismos, en los que se aplica cualquier combinacion coherente de dos o mas seleccionados del grupo que consiste en (1-5), (1-7), (1-8), (2-6), (2-7), (2-8), (2-9), (2-10), (2-11), (2-12), (2-13), (2-14), (3-9), (3-10), (3-11) y (4) mostrados anteriormente.(5-9) Compounds or a salt thereof, in which any coherent combination of two or more selected from the group consisting of (1-5), (1-7), (1-8), ( 2-6), (2-7), (2-8), (2-9), (2-10), (2-11), (2-12), (2-13), (2- 14), (3-9), (3-10), (3-11) and (4) shown above.

Otras realizaciones del compuesto de formula (I) o una sal del mismo se dan a continuacion.Other embodiments of the compound of formula (I) or a salt thereof are given below.

(6) Compuestos de formula (I) o una sal de los mismos, en la que(6) Compounds of formula (I) or a salt thereof, in which

(6-2) -X- es un grupo de formula (II), y A es etilo o isopropilo,(6-2) -X- is a group of formula (II), and A is ethyl or isopropyl,

(6-3) -X- es un grupo de formula (II), y A es etilo, o (6-4) -X- es un grupo de formula (II), y A es isopropilo.(6-3) -X- is a group of formula (II), and A is ethyl, or (6-4) -X- is a group of formula (II), and A is isopropyl.

(7) Compuestos de formula (I) o una sal de los mismos, en la que(7) Compounds of formula (I) or a salt thereof, in which

(7-2) R1 es fenilo en el que el carbono en la posicion 4 esta sustituido con -W-Y-Z y, como otro sustituyente, el carbono en el carbono en la posicion 3 puede estar sustituido con R00 o -O- R00, -W- es piperidin-1,4-dnlo (unido mediante el atomo de nitrogeno al fenilo al que esta unido - W-) o un enlace, -Y- es un enlace y -Z es piperazin-1-ilo en el que el atomo de nitrogeno en la posicion 4 puede estar sustituido con alquilo inferior,(7-2) R1 is phenyl in which the carbon in position 4 is substituted with -WYZ and, as another substituent, the carbon in the carbon in position 3 may be substituted with R00 or -O- R00, -W - is piperidin-1,4-dnlo (linked by the nitrogen atom to the phenyl to which it is attached - W-) or a bond, -Y- is a bond and -Z is piperazin-1-yl in which the atom of nitrogen in position 4 may be substituted with lower alkyl,

(7-3) R1 es fenilo en el que el carbono en la posicion 4 esta sustituido con 4-(4-metilpiperazin-1-il)piperidin-1-ilo y, como otro sustituyente, el carbono en la posicion 3 puede estar sustituido con metilo, trifluorometilo, metoxi o etoxi,(7-3) R1 is phenyl in which the carbon in position 4 is substituted with 4- (4-methylpiperazin-1-yl) piperidin-1-yl and, as another substituent, the carbon in position 3 may be substituted with methyl, trifluoromethyl, methoxy or ethoxy,

(7-4) R1 es 3-metil-4-{4-(4-metilpiperazin-1-il)piperidin-1-il}fenilo,(7-4) R1 is 3-methyl-4- {4- (4-methylpiperazin-1-yl) piperidin-1-yl} phenyl,

(7-5) R1 es 4-{4-(4-metilpiperazin-1-il)piperidin-1-il}-3-(trifluorometil)fenilo,(7-5) R1 is 4- {4- (4-methylpiperazin-1-yl) piperidin-1-yl} -3- (trifluoromethyl) phenyl,

(7-6) R1 es 3-metoxi-4-{4-(4-metilpiperazin-1-il)piperidin-1-il}fenilo,(7-6) R1 is 3-methoxy-4- {4- (4-methylpiperazin-1-yl) piperidin-1-yl} phenyl,

(7-7) R1 es 3-etoxi-4-{4-(4-metilpiperazin-1-il)piperidin-1-il}fenilo,(7-7) R1 is 3-ethoxy-4- {4- (4-methylpiperazin-1-yl) piperidin-1-yl} phenyl,

(7-8) R1 es 4-{4-(4-metilpiperazin-1-il)piperidin-1-il}fenilo,(7-8) R1 is 4- {4- (4-methylpiperazin-1-yl) piperidin-1-yl} phenyl,

(7-9) R1 es fenilo en el que el carbono en la posicion 4 esta sustituido con 4-metilpiperazin-1-ilo o 4- isopropilpiperazin-1-ilo y, como otro sustituyente, el carbono en la posicion 3 puede estar sustituido con metilo, trifluorometilo o metoxi,(7-9) R1 is phenyl in which the carbon in position 4 is substituted with 4-methylpiperazin-1-yl or 4- isopropylpiperazin-1-yl and, as another substituent, the carbon in position 3 may be substituted with methyl, trifluoromethyl or methoxy,

(7-10) R1 es 3-metil-4-(4-metilpiperazin-1-il)fenilo,(7-10) R1 is 3-methyl-4- (4-methylpiperazin-1-yl) phenyl,

(7-11) R1 es 4-(4-metilpiperazin-1-il)-3-(trifluorometil)fenilo,(7-11) R1 is 4- (4-methylpiperazin-1-yl) -3- (trifluoromethyl) phenyl,

(7-12) R1 es 3-metoxi-4-(4-metilpiperazin-1-il)fenilo,(7-12) R1 is 3-methoxy-4- (4-methylpiperazin-1-yl) phenyl,

(7-13) R1 es 4-(4-metilpiperazin-1-il)fenilo,(7-13) R1 is 4- (4-methylpiperazin-1-yl) phenyl,

(7-14) R1 es 4-(4-isopropilpiperazin-1-il)-3-metilfenilo,(7-14) R1 is 4- (4-isopropylpiperazin-1-yl) -3-methylphenyl,

(7-15) R1 es fenilo en el que el carbono en la posicion 3 esta sustituido con -SO2-R00,(7-15) R1 is phenyl in which the carbon in position 3 is substituted with -SO2-R00,

(7-16) R1 es 3-(metilsulfonil)fenilo,(7-16) R1 is 3- (methylsulfonyl) phenyl,

(7-21) R1 es 2-metoxi-4-{4-(4-metilpiperazin-1-il)piperidin-1-il}fenilo,(7-21) R1 is 2-methoxy-4- {4- (4-methylpiperazin-1-yl) piperidin-1-yl} phenyl,

(7-23) R1 es 4-morfolin-4-ilfenilo,(7-23) R1 is 4-morpholin-4-ylphenyl,

(7-24) R1 es 4-(1-metilpiperidin-4-il)fenilo,(7-24) R1 is 4- (1-methylpiperidin-4-yl) phenyl,

(7-25) R1 es 4-{4-(ciclopropilmetil)piperazin-1-il}-3-(trifluorometil)fenilo, o (7-26) R1 es 4-{3-(dimetilamino)pirrolidin-1-il}-3-(trifluorometil)fenilo.(7-25) R1 is 4- {4- (cyclopropylmethyl) piperazin-1-yl} -3- (trifluoromethyl) phenyl, or (7-26) R1 is 4- {3- (dimethylamino) pyrrolidin-1-yl } -3- (trifluoromethyl) phenyl.

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(8) Compuestos de formula (I) o una sal de los mismos, en los que(8) Compounds of formula (I) or a salt thereof, in which

(8-1) R2 es cicloalquilo sustituido con -OH y alquilo inferior,(8-1) R2 is cycloalkyl substituted with -OH and lower alkyl,

(8-2) R2 es ciclohexilo sustituido con -OH y alquilo inferior,(8-2) R2 is cyclohexyl substituted with -OH and lower alkyl,

(8-3) R2 es ciclohexilo en el que el carbono en la posicion 4 esta sustituido con -OH y alquilo inferior,(8-3) R2 is cyclohexyl in which the carbon in position 4 is substituted with -OH and lower alkyl,

(8-4) R2 es ciclohexilo en el que el carbono en la posicion 4 esta sustituido con -OH y metilo,(8-4) R2 is cyclohexyl in which the carbon in position 4 is substituted with -OH and methyl,

(8-5) R2 es cicloalquilo sustituido con -OH,(8-5) R2 is cycloalkyl substituted with -OH,

(8-6) R2 es ciclohexilo sustituido con -OH,(8-6) R2 is cyclohexyl substituted with -OH,

(8-7) R2 es 4-hidroxiciclohexilo,(8-7) R2 is 4-hydroxycyclohexyl,

(8-8) R2 es un anillo heterodclico no aromatico que puede estar sustituido con alquilo inferior,(8-8) R2 is a non-aromatic heterodclic ring that may be substituted with lower alkyl,

(8-9) R2 es tetrahidropiranilo que puede estar sustituido con alquilo inferior, o piperidinilo que puede estar sustituido con alquilo inferior,(8-9) R2 is tetrahydropyranyl which may be substituted with lower alkyl, or piperidinyl which may be substituted with lower alkyl,

(8-10) R2 es tetrahidropiran-4-ilo,(8-10) R2 is tetrahydropyran-4-yl,

(8-11) R2 es piperidin-4-ilo en que el atomo de nitrogeno en la posicion 1 puede estar sustituido con alquilo inferior,(8-11) R2 is piperidin-4-yl in which the nitrogen atom in position 1 may be substituted with lower alkyl,

(8-12) R2 es 1 -metilpiperidin-4-ilo, o (8-13) R2 es piperidin-4-ilo.(8-12) R2 is 1-methylpiperidin-4-yl, or (8-13) R2 is piperidin-4-yl.

(9) Compuestos de formula (I) o una sal de los mismos, en la que R3 es -H.(9) Compounds of formula (I) or a salt thereof, wherein R3 is -H.

(10) Compuestos de (6-3) mostrados anteriormente o una sal de los mismos.(10) Compounds of (6-3) shown above or a salt thereof.

(11) Compuestos de (7-4), (7-5), (7-6), (7-7), (7-8), (7-10), (7-13) o (7-14) mostrados anteriormente o una sal de los mismos.(11) Compounds of (7-4), (7-5), (7-6), (7-7), (7-8), (7-10), (7-13) or (7- 14) shown above or a salt thereof.

(12) Compuestos de (8-4), (8-7), (8-10) o (8-13) mostrados anteriormente o una sal de los mismos.(12) Compounds of (8-4), (8-7), (8-10) or (8-13) shown above or a salt thereof.

(13) Compuestos, en los que(13) Compounds, in which

(13-1) se aplica cualquier combinacion de dos o mas de (6) a (9) mostrados anteriormente, o una sal de los mismos, o(13-1) any combination of two or more of (6) to (9) shown above, or a salt thereof, or

(13-2) se aplica cualquier combinacion de dos o mas de (9) a (12) mostrados anteriormente, o una sal de los mismos.(13-2) any combination of two or more of (9) to (12) shown above, or a salt thereof, is applied.

Ejemplos de compuestos espedficos que entran dentro de la presente invencion incluyen los siguientes compuestos.Examples of specific compounds that fall within the present invention include the following compounds.

6-etil-5-[(trans-4-hidroxiciclohexil)amino]-3-{[4-(4-metilpiperazin-1-il)fenil]amino}pirazin-2-carboxamida,6-ethyl-5 - [(trans-4-hydroxycyclohexyl) amino] -3 - {[4- (4-methylpiperazin-1-yl) phenyl] amino} pyrazin-2-carboxamide,

6-etil-5-[(trans-4-hidroxiciclohexil)amino]-3-({4-[4-(4-metilpiperazin-1-il)piperidin-1-il]fenil}amino)pirazin-2-6-ethyl-5 - [(trans-4-hydroxycyclohexyl) amino] -3 - ({4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} amino) pyrazin-2-

carboxamida,carboxamide,

5- [(trans-4-hidroxiciclohexil)amino]-6-isopropil-3-{[4-(4-metilpiperazin-1-il)fenil]amino}pirazin-2-carboxamida,5- [(trans-4-hydroxycyclohexyl) amino] -6-isopropyl-3 - {[4- (4-methylpiperazin-1-yl) phenyl] amino} pyrazin-2-carboxamide,

6- etil-5-[(trans-4-hidroxiciclohexil)amino]-3-({4-[4-(4-metilpiperazin-1-il)piperidin-1-il]-3- (trifluorometil)fenil}amino)pirazin-2-carboxamida,6- ethyl-5 - [(trans-4-hydroxycyclohexyl) amino] -3 - ({4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] -3- (trifluoromethyl) phenyl} amino ) pyrazin-2-carboxamide,

6-etil-5-[(trans-4-hidroxiciclohexil)amino]-3-({3-metil-4-[4-(4-metilpiperazin-1-il)piperidin-1-il]fenil}amino)pirazin-2-6-ethyl-5 - [(trans-4-hydroxycyclohexyl) amino] -3 - ({3-methyl-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} amino) pyrazine -2-

carboxamida,carboxamide,

5- [(trans-4-hidroxiciclohexil)amino]-6-isopropil-3-({4-[4-(4-metilpiperazin-1-il)piperidin-1-il]-3- (trifluorometil)fenil}amino)pirazin-2-carboxamida,5- [(trans-4-hydroxycyclohexyl) amino] -6-isopropyl-3 - ({4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] -3- (trifluoromethyl) phenyl} amino ) pyrazin-2-carboxamide,

6- etil-5-[(cis-4-hidroxi-4-metilciclohexil)amino]-3-({3-metil-4-[4-(4-metilpiperazin-1-il)piperidin-1-il]fenil}amino)pirazin-2- carboxamida,6- ethyl-5 - [(cis-4-hydroxy-4-methylcyclohexyl) amino] -3 - ({3-methyl-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl } amino) pyrazin-2-carboxamide,

6-etil-5-[(trans-4-hidroxiciclohexil)amino]-3-{[4-(4-isopropilpiperazin-1-il)-3-metilfenil]amino}pirazin-2-carboxamida,6-ethyl-5 - [(trans-4-hydroxycyclohexyl) amino] -3 - {[4- (4-isopropylpiperazin-1-yl) -3-methylphenyl] amino} pyrazin-2-carboxamide,

6-etil-5-[(trans-4-hidroxi-4-metilciclohexil)amino]-3-({3-metil-4-[4-(4-metilpiperazin-1-il)piperidin-1-6-ethyl-5 - [(trans-4-hydroxy-4-methylcyclohexyl) amino] -3 - ({3-methyl-4- [4- (4-methylpiperazin-1-yl) piperidin-1-

il]fenil}amino)pirazin-2-carboxamida,il] phenyl} amino) pyrazin-2-carboxamide,

6-etil-3-({3-metil-4-[4-(4-metilpiperazin-1-il)piperidin-1-il]fenil}amino)-5-(tetrahidro-2H-piran-4-ilamino)pirazin-2-6-ethyl-3 - ({3-methyl-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} amino) -5- (tetrahydro-2H-pyran-4-ylamino) pyrazin-2-

carboxamida,carboxamide,

6-cloro-5-[(trans-4-hidroxiciclohexil)amino]-3-({3-metil-4-[4-(4-metilpiperazin-1-il)piperidin-1-il]fenil}amino)pirazin-2-6-chloro-5 - [(trans-4-hydroxycyclohexyl) amino] -3 - ({3-methyl-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} amino) pyrazine -2-

carboxamida,carboxamide,

6-etil-3-({4-[4-(4-metilpiperazin-1-il)piperidin-1-il]fenil}amino)-5-(tetrahidro-2H-piran-4-ilamino)pirazin-2-carboxamida,6-ethyl-3 - ({4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} amino) -5- (tetrahydro-2H-piran-4-ylamino) pyrazin-2- carboxamide,

6-etil-3-({3-metoxi-4-[4-(4-metilpiperazin-2-il)piperidin-1-il]fenil}amido)-5-(tetrahidro-2H-piran-4-ilamino)pirazin-2-6-ethyl-3 - ({3-methoxy-4- [4- (4-methylpiperazin-2-yl) piperidin-1-yl] phenyl} amido) -5- (tetrahydro-2H-pyran-4-ylamino) pyrazin-2-

carboxamida,carboxamide,

6-isopropil-3-({4-[4-(4-metilpiperazin-1-il)piperidin-1-il]fenil}amino)-5-(tetrahidro-2H-piran-4-ilamino)pirazin-2-6-Isopropyl-3 - ({4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} amino) -5- (tetrahydro-2H-pyran-4-ylamino) pyrazin-2-

carboxamida,carboxamide,

6-etil-3-{[3-fluoro-4-(4-metilpiperazin-1-il)fenil]amino}-5-(tetrahidro-2H-piran-4-ilamino)pirazin-2-carboxamida, 6-isopropil-3-[3-metoxi-4-(4-metilpiperazin-1-il)fenil]amino}-5-(tetrahidro-2H-piran-4-ilamino)pirazin-2-carboxamida. 6-isopropil-3-{[4-(4-metilpiperazin-1-il)fenil]amino}-5-(tetrahidro-2H-piran-4-ilamino)pirazin-2-carboxamida, o 6-etil-3-({3-metil-4-[4-(1-metilpiperidin-4-il)piperazin-1-il]fenil}amino)-5-(tetrahidro-2H-piran-4-ilamino)pirazin-2- carboxamida, o una sal de los mismos.6-ethyl-3 - {[3-fluoro-4- (4-methylpiperazin-1-yl) phenyl] amino} -5- (tetrahydro-2H-pyran-4-ylamino) pyrazin-2-carboxamide, 6-isopropyl -3- [3-Methoxy-4- (4-methylpiperazin-1-yl) phenyl] amino} -5- (tetrahydro-2H-pyran-4-ylamino) pyrazin-2-carboxamide. 6-Isopropyl-3 - {[4- (4-methylpiperazin-1-yl) phenyl] amino} -5- (tetrahydro-2H-pyran-4-ylamino) pyrazin-2-carboxamide, or 6-ethyl-3- ({3-methyl-4- [4- (1-methylpiperidin-4-yl) piperazin-1-yl] phenyl} amino) -5- (tetrahydro-2H-pyran-4-ylamino) pyrazine-2-carboxamide, or a salt thereof.

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Ejemplos de compuestos espedficos que entran dentro de la presente invencion incluyen aquellos seleccionados de los grupos de compuestos P y Q mostrados a continuacion.Examples of specific compounds that fall within the present invention include those selected from the groups of compounds P and Q shown below.

Grupo de compuestos P:Group of compounds P:

un grupo que consiste en 6-etil-5-[(trans-4-hidroxiciclohexil)amino]-3-({4-[4-(4-metilpiperazin-1-il)piperidin-1- il]fenil}amino)pirazin-2-carboxamida.a group consisting of 6-ethyl-5 - [(trans-4-hydroxycyclohexyl) amino] -3 - ({4- [4- (4-methylpiperazin-1-yl) piperidin-1- yl] phenyl} amino) pyrazin-2-carboxamide.

6-etil-5-[(trans-4-hidroxiciclohexil)amino]-3-{[4-(4-metilpiperazin-1-il)-3-(trifluorometil)fenil]amino}pirazin-2-6-ethyl-5 - [(trans-4-hydroxycyclohexyl) amino] -3 - {[4- (4-methylpiperazin-1-yl) -3- (trifluoromethyl) phenyl] amino} pyrazin-2-

carboxamida,carboxamide,

6-etil-5-[(trans-4-hidroxiciclohexil)amino]-3-({4-[4-(4-metilpiperazin-1-il)piperidin-1-il]-3-6-ethyl-5 - [(trans-4-hydroxycyclohexyl) amino] -3 - ({4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] -3-

(trifluorometil)fenil}amino)pirazin-2-carboxamida,(trifluoromethyl) phenyl} amino) pyrazin-2-carboxamide,

6-etil-5-[(trans-4-hidroxiciclohexil)amino]-3-{[3-metil-4-(4-metilpiperazin-1-il)fenil]amino}pirazin-2-carboxamida,6-ethyl-5 - [(trans-4-hydroxycyclohexyl) amino] -3 - {[3-methyl-4- (4-methylpiperazin-1-yl) phenyl] amino} pyrazin-2-carboxamide,

6-etil-5-[(trans-4-hidroxiciclohexil)amino]-3-({3-metil-4-[4-(4-metilpiperazin-1-il)piperidin-1-il]fenil}amino)pirazin-2-6-ethyl-5 - [(trans-4-hydroxycyclohexyl) amino] -3 - ({3-methyl-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} amino) pyrazine -2-

carboxamida,carboxamide,

6-etil-5-[(cis-4-hidroxi-4-metilciclohexil)amino]-3-({3-metil-4-[4-(4-metilpiperazin-1-il)piperidin-1-il]fenil}amino)pirazin-2-6-ethyl-5 - [(cis-4-hydroxy-4-methylcyclohexyl) amino] -3 - ({3-methyl-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl } amino) pyrazin-2-

carboxamida,carboxamide,

6-etil-5-[(trans-4-hidroxiciclohexil)amino]-3-{[4-(4-isopropilpiperazin-1-il)-3-metilfenil]amino}pirazin-2-carboxamida,6-ethyl-5 - [(trans-4-hydroxycyclohexyl) amino] -3 - {[4- (4-isopropylpiperazin-1-yl) -3-methylphenyl] amino} pyrazin-2-carboxamide,

3-({3-etoxi-4-[4-(4-metilpiperazin-1-il)piperidin-1-il]fenil}amino)-6-etil-5-[(trans-4-hidroxiciclohexil)amino]pirazin-2-3 - ({3-ethoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} amino) -6-ethyl-5 - [(trans-4-hydroxycyclohexyl) amino] pyrazin -2-

carboxamida,carboxamide,

6-etil-5-[(trans-4-hidroxi-4-metilciclohexil)amino]-3-({3-metil-4-[4-(4-metilpiperazin-1-il)piperidin-1-6-ethyl-5 - [(trans-4-hydroxy-4-methylcyclohexyl) amino] -3 - ({3-methyl-4- [4- (4-methylpiperazin-1-yl) piperidin-1-

il]fenil}amino)pirazin-2-carboxamida,il] phenyl} amino) pyrazin-2-carboxamide,

6-etil-3-({3-metil-4-[4-(4-metilpiperazin-1-il)piperidin-1-il]fenil}amino)-5-(tetrahidro-2H-piran-4-ilamino)pirazin-2-6-ethyl-3 - ({3-methyl-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} amino) -5- (tetrahydro-2H-pyran-4-ylamino) pyrazin-2-

carboxamida,carboxamide,

6-etil-3-({3-metil-4-[4-(4-metilpiperazin-1-il)piperidin-1-il]fenil}amino)-5-(piperidin-4-ilamino)pirazin-2-carboxamida,6-ethyl-3 - ({3-methyl-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} amino) -5- (piperidin-4-ylamino) pyrazin-2- carboxamide,

6-etil-3-{[4-(4-metilpiperazin-2-il)fenil]amino}-5-{tetrahidro-2H-piran-4-ilamino)pirazin-2-carboxamida,6-ethyl-3 - {[4- (4-methylpiperazin-2-yl) phenyl] amino} -5- {tetrahydro-2H-pyran-4-ylamino) pyrazin-2-carboxamide,

6-etil-3-({4-[4-(4-metilpiperazin-1-il)piperidin-1-il]fenil}amino)-5-(tetrahidro-2H-piran-4-ilamino)pirazin-2-carboxamida,6-ethyl-3 - ({4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} amino) -5- (tetrahydro-2H-piran-4-ylamino) pyrazin-2- carboxamide,

yY

6-etil-3-({3-metoxi-4-[4-(4-metilpiperazin-1-il)pipendin-1-il]fenil}amino)-5-(tetrahidro-2H-piran-4-ilamino)pirazin-2- carboxamida, ademas de sales de estos compuestos.6-ethyl-3 - ({3-methoxy-4- [4- (4-methylpiperazin-1-yl) pipendin-1-yl] phenyl} amino) -5- (tetrahydro-2H-pyran-4-ylamino) pyrazin-2-carboxamide, in addition to salts of these compounds.

Grupo de compuestos Q:Group of compounds Q:

un grupo que consiste en 6-etil-5-[(trans-4-hidroxiciclohexil)amino]-3-{[3-(metilsulfonil)fenil]amino}pirazin-2- carboxamida,a group consisting of 6-ethyl-5 - [(trans-4-hydroxycyclohexyl) amino] -3 - {[3- (methylsulfonyl) phenyl] amino} pyrazine-2-carboxamide,

6-etil-5-[(trans-4-hidroxi-4-metilciclohexil)amino]-3-{[3-(metilsulfonil)fenil]amino}pirazin-2-carboxamida,6-ethyl-5 - [(trans-4-hydroxy-4-methylcyclohexyl) amino] -3 - {[3- (methylsulfonyl) phenyl] amino} pyrazin-2-carboxamide,

6-etil-5-[(trans-4-hidroxiciclohexil)amino]-3-({2-metoxi-4-[4-(4-metilpiperazin-1-il)piperidin-1-il]fenil}amino)pirazin-2-6-ethyl-5 - [(trans-4-hydroxycyclohexyl) amino] -3 - ({2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} amino) pyrazine -2-

carboxamida,carboxamide,

6-etil-5-[(trans-4-hidroxiciclohexil)amino]-3-{[4-(4-metilpiperazin-1-il)fenil]amino}pirazin-2-carboxamida,6-ethyl-5 - [(trans-4-hydroxycyclohexyl) amino] -3 - {[4- (4-methylpiperazin-1-yl) phenyl] amino} pyrazin-2-carboxamide,

6-etil-5-[(trans-4-hidroxiciclohexil)amino]-3-[(1-metil-lH-indazol-6-il)amino]pirazin-2-carboxamida,6-ethyl-5 - [(trans-4-hydroxycyclohexyl) amino] -3 - [(1-methyl-lH-indazol-6-yl) amino] pyrazin-2-carboxamide,

6-etil-5-[(trans-4-hidroxiciclohexil)amino]-3-({3-metoxi-4-[4-(4-metilpiperazin-1-il)piperidin-1-il]fenil}amino)pirazin-2-6-ethyl-5 - [(trans-4-hydroxycyclohexyl) amino] -3 - ({3-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} amino) pyrazine -2-

carboxamida,carboxamide,

5- [(trans-4-hidroxiciclohexil)amino]-6-isopropil-3-{[4-(4-metilpiperazin-1-il)fenil]amino}pirazin-2-carboxamida,5- [(trans-4-hydroxycyclohexyl) amino] -6-isopropyl-3 - {[4- (4-methylpiperazin-1-yl) phenyl] amino} pyrazin-2-carboxamide,

6- etil-5-[(trans-4-hidroxiciclohexil)amino]-3-{[3-(4-metilpiperazin-1-il)fenil]amino}pirazin-2-carboxamida, 6-etil-5-[(trans-4-hidroxiciclohexil)amino]-3-{[3-metoxi-4-(4-metilpiperazin-1-il)fenil]amino}pirazin-2-carboxamida, 6-etil-5-[(trans-4-hidroxiciclohexil)amino]-3-[(4-morfolin-4-ilfenil)amino]pirazin-2-carboxamida, 6-etil-5-[(trans-4-hidroxiciclohexil)amino]-3-{[4-metoxi-3-(4-metilpiperazin-1-il)fenil]amino}pirazin-2-carboxamida, 6-etil-5-[(trans-4-hidroxiciclohexil)amino]-3-{[4-(1-metilpiperidin-4-il)fenil]amino}pirazin-2-carboxamida,6- ethyl-5 - [(trans-4-hydroxycyclohexyl) amino] -3 - {[3- (4-methylpiperazin-1-yl) phenyl] amino} pyrazin-2-carboxamide, 6-ethyl-5 - [( trans-4-hydroxycyclohexyl) amino] -3 - {[3-methoxy-4- (4-methylpiperazin-1-yl) phenyl] amino} pyrazin-2-carboxamide, 6-ethyl-5 - [(trans-4- hydroxycyclohexyl) amino] -3 - [(4-morpholin-4-ylphenyl) amino] pyrazin-2-carboxamide, 6-ethyl-5 - [(trans-4-hydroxycyclohexyl) amino] -3 - {[4-methoxy- 3- (4-methylpiperazin-1-yl) phenyl] amino} pyrazin-2-carboxamide, 6-ethyl-5 - [(trans-4-hydroxycyclohexyl) amino] -3 - {[4- (1-methylpiperidin-4 -yl) phenyl] amino} pyrazin-2-carboxamide,

5- [(trans-4-hidroxiciclohexil)amino]-6-isopropil-3-({4-[4-(4-metilpiperazin-1-il)piperidin-1-il]-3- (trifluorometil)fenil}amino)pirazin-2-carboxamida,5- [(trans-4-hydroxycyclohexyl) amino] -6-isopropyl-3 - ({4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] -3- (trifluoromethyl) phenyl} amino ) pyrazin-2-carboxamide,

6- etil-5-[(cis-4-hidroxi-4-metilciclohexil)amino]-3-{[3-metil-4-(4-metilpiperazin-1-il)fenil]amino}pirazin-2-carboxamida, 3-({4-[4-(ciclopropilmetil)piperazin-1-il]-3-(trifluorometil)fenil}amino)-6-etil-5-[(trans-4-hidroxiciclohexil)amino]pirazin-2- carboxamida,6- ethyl-5 - [(cis-4-hydroxy-4-methylcyclohexyl) amino] -3 - {[3-methyl-4- (4-methylpiperazin-1-yl) phenyl] amino} pyrazin-2-carboxamide, 3 - ({4- [4- (cyclopropylmethyl) piperazin-1-yl] -3- (trifluoromethyl) phenyl} amino) -6-ethyl-5 - [(trans-4-hydroxycyclohexyl) amino] pyrazine-2-carboxamide ,

3-({4-[3-(dimetilamino)pirrolidin-1-il]-3-(trifluorometil)fenil}amino)-6-etil-5-[(trans-4-hidroxiciclohexil)amino]pirazin-2-3 - ({4- [3- (dimethylamino) pyrrolidin-1-yl] -3- (trifluoromethyl) phenyl} amino) -6-ethyl-5 - [(trans-4-hydroxycyclohexyl) amino] pyrazin-2-

carboxamida,carboxamide,

6-etil-5-[(cis-4-etil-4-hidroxiciclohexil)amino]-3-({3-metil-4-[4-(4-metilpiperazin-1-il)piperidin-1-il]fenil}amino)pirazin-2-6-ethyl-5 - [(cis-4-ethyl-4-hydroxycyclohexyl) amino] -3 - ({3-methyl-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl } amino) pyrazin-2-

carboxamida,carboxamide,

6-etil-5-[(trans-4-etil-4-hidroxiciclohexil)amino]-3-({3-metil-4-[4-(4-metilpiperazin-1-il)piperidin-1-il]fenil}amino)pirazin-6-ethyl-5 - [(trans-4-ethyl-4-hydroxycyclohexyl) amino] -3 - ({3-methyl-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl } amino) pyrazin-

2-carboxamida,2-carboxamide,

6-etil-5-[(cis-4-hidroxi-4-isopropilciclohexil)amino]-3-({3-metil-4-[4-(4-metilpiperazin-1-il)piperidin-1-6-ethyl-5 - [(cis-4-hydroxy-4-isopropylcyclohexyl) amino] -3 - ({3-methyl-4- [4- (4-methylpiperazin-1-yl) piperidin-1-

il]fenil}amino)pirazin-2-carboxamida,il] phenyl} amino) pyrazin-2-carboxamide,

6-etil-5-[(trans-4-hidroxi-4-isopropilciclohexil)amino]-3-({3-metil-4-(4-(4-metilpiperazin-1-il)piperidin-1- il]fenil}amino)pirazin-2-carboxamida, y6-ethyl-5 - [(trans-4-hydroxy-4-isopropylcyclohexyl) amino] -3 - ({3-methyl-4- (4- (4-methylpiperazin-1-yl) piperidin-1- yl] phenyl } amino) pyrazin-2-carboxamide, and

6-etil-3-(3-metil-4-[4-(4-metilpiperazin-1-il)piperidin-1-il]fenil}amino)-5-[(1-metilpiperidin-4-il)amino]pirazin-2- carboxamida, ademas de sales de estos compuestos.6-ethyl-3- (3-methyl-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} amino) -5 - [(1-methylpiperidin-4-yl) amino] pyrazin-2-carboxamide, in addition to salts of these compounds.

Los compuestos de formula (I) pueden tener tautomeros y/o isomeros geometricos (incluyendo isomeros cis-trans de compuestos que tienen un grupo de anillo saturado tal como un grupo cicloalquilo), dependiendo del tipo de sus sustituyentes. Incluso cuando los compuestos de formula (I) aparecen en el presente documento solo en una formaThe compounds of formula (I) may have tautomers and / or geometric isomers (including cis-trans isomers of compounds having a saturated ring group such as a cycloalkyl group), depending on the type of their substituents. Even when the compounds of formula (I) appear herein only in one form

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de isomero, la presente invencion engloba los otros isomeros, y tambien engloba isomeros separados o mezclas de los mismos.of isomer, the present invention encompasses the other isomers, and also encompasses separate isomers or mixtures thereof.

Ademas, como algunos compuestos de formula (I) tienen un atomo de carbono asimetrico o asimetria axial, tambien pueden existir isomeros opticos basados en esta asimetria. La presente invencion tambien engloba isomeros opticos separados de los compuestos de formula (I) o mezclas de los mismos.In addition, since some compounds of formula (I) have an asymmetric carbon atom or axial asymmetry, there may also be optical isomers based on this asymmetry. The present invention also encompasses separate optical isomers of the compounds of formula (I) or mixtures thereof.

Asimismo, sales de los compuestos de formula (I) son sales farmaceuticamente aceptables de los compuestos de formula (I). Los compuestos de formula (I) pueden formar sales de adicion de acido o de base, dependiendo del tipo de sus sustituyentes. Ejemplos espedficos incluyen sales de adicion de acido con acidos inorganicos (por ejemplo, acido clorddrico, acido bromddrico, acido yodddrico, acido sulfurico, acido dtrico, acido fosforico y similares) o con acidos organicos (por ejemplo, acido formico, acido acetico, acido propionico, acido oxalico, acido malonico, acido sucdnico, acido fumarico, acido maleico, acido lactico, acido malico, acido mandelico, acido tartarico, acido dibenzoiltartarico, acido ditoluoiltartarico, acido dtrico, acido metanosulfonico, acido etanosulfonico, acido bencenosulfonico, acido p-toluenosulfonico, acido aspartico, acido glutamico, y similares), sales con bases inorganicas (por ejemplo, sodio, potasio, magnesio, calcio, aluminio y similares) o con bases organicas (por ejemplo, metilamina, etilamina, etanolamina, lisina, ornitina y similares), sales con diversos aminoacidos y derivados de aminoacidos (por ejemplo, acetil-leucina, y similares), ademas de sal de amonio, etc.Also, salts of the compounds of formula (I) are pharmaceutically acceptable salts of the compounds of formula (I). The compounds of formula (I) may form acid or base addition salts, depending on the type of their substituents. Specific examples include acid addition salts with inorganic acids (for example, chloric acid, hydrochloric acid, iodine acid, sulfuric acid, dric acid, phosphoric acid and the like) or with organic acids (for example, formic acid, acetic acid, acid propionic, oxalic acid, malonic acid, sucdnic acid, smoking acid, maleic acid, lactic acid, maolic acid, mandelic acid, tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid, dric acid, methanesulfonic acid, ethanesulfonic acid, ethanesulfonic acid toluenesulfonic acid, aspartic acid, glutamic acid, and the like), salts with inorganic bases (for example, sodium, potassium, magnesium, calcium, aluminum and the like) or with organic bases (for example, methylamine, ethylamine, ethanolamine, lysine, ornithine and similar), salts with various amino acids and amino acid derivatives (for example, acetyl-leucine, and the like), in addition to ammonium salt, etc.

Ademas, la presente invencion tambien engloba los compuestos de formula (I) y sales de los mismos en forma de diversos hidratos, solvatos y sustancias polimorficas cristalinas. La presente invencion tambien engloba los compuestos marcados con diversos isotopos radiactivos o no radiactivos.In addition, the present invention also encompasses the compounds of formula (I) and salts thereof in the form of various hydrates, solvates and crystalline polymorphic substances. The present invention also encompasses compounds labeled with various radioactive or non-radioactive isotopes.

Los compuestos de formula (I) y sales farmaceuticamente aceptables de los mismos pueden prepararse aplicando diversos metodos de smtesis conocidos basandose en caracteristicas derivadas de su estructura esqueletica o el tipo de sus sustituyentes. En algunos casos, dependiendo del tipo de grupo funcional, es tecnicamente eficaz sustituir un grupo funcional tal con un grupo protector apropiado (un grupo que puede convertirse facilmente en el grupo funcional original) en la etapa de material de partida o en la etapa de producto intermedio. Ejemplos de un grupo protector tal incluyen aquellos descritos en Greene y Wuts, “Greene's Protective Groups in Organic Synthesis (cuarta edicion, 2007)”, etc., que pueden seleccionarse y usarse segun convenga, dependiendo de las condiciones de reaccion. En un metodo tal, despues de la introduccion del grupo protector y la posterior reaccion, el grupo protector puede eliminarse si fuera necesario para obtener un compuesto deseado.The compounds of formula (I) and pharmaceutically acceptable salts thereof can be prepared by applying various known methods of synthesis based on characteristics derived from their skeletal structure or the type of their substituents. In some cases, depending on the type of functional group, it is technically effective to replace such a functional group with an appropriate protective group (a group that can easily become the original functional group) in the starting material stage or in the product stage intermediate. Examples of such a protecting group include those described in Greene and Wuts, "Greene's Protective Groups in Organic Synthesis (fourth edition, 2007)", etc., which may be selected and used as appropriate, depending on the reaction conditions. In such a method, after the introduction of the protective group and the subsequent reaction, the protective group can be removed if necessary to obtain a desired compound.

Asimismo, puede prepararse un profarmaco del compuesto de formula (I) introduciendo un grupo espedfico en la etapa de material de partida o en la etapa de producto intermedio, como en el caso del grupo protector anterior, o sometiendo el compuesto obtenido de formula (I) a reaccion adicional. La reaccion puede llevarse a cabo aplicando tecnicas convencionales de esterificacion, amidacion, deshidratacion u otras tecnicas conocidas para aquellos expertos en la materia.Likewise, a prodrug of the compound of formula (I) can be prepared by introducing a specific group in the starting material stage or in the intermediate product stage, as in the case of the previous protecting group, or by subjecting the compound obtained from formula (I ) to additional reaction. The reaction can be carried out by applying conventional techniques of esterification, amidation, dehydration or other techniques known to those skilled in the art.

A continuacion se dara una explicacion de procesos ripicos para preparar los compuestos de formula (I). Cada proceso tambien puede llevarse a cabo por referencia a los documentos citados en esta explicacion. Debe observarse que los procesos de la presente invencion no se limitan a los ejemplos ilustrados a continuacion.An explanation of typical processes for preparing the compounds of formula (I) will be given below. Each process can also be carried out by reference to the documents cited in this explanation. It should be noted that the processes of the present invention are not limited to the examples illustrated below.

(Proceso de preparacion 1) (no es parte de la invencion)(Preparation process 1) (not part of the invention)

imagen23image23

(En la formula, -LA representa un grupo saliente, y ejemplos incluyen alquil inferior-sulfanilo)(In the formula, -LA represents a leaving group, and examples include lower alkyl sulfanyl)

Este proceso pretende preparar el compuesto de la presente invencion (I-a) haciendo reaccionar el compuesto (1a) con el compuesto (2).This process is intended to prepare the compound of the present invention (I-a) by reacting the compound (1a) with the compound (2).

En esta reaccion, los compuestos (1a) y (2) se usan en cantidades iguales o uno de ellos se usa en una cantidad excesiva. Una mezcla de estos compuestos se agita en un disolvente inerte para la reaccion o en ausencia de un disolvente con condiciones de enfriamiento a reflujo, preferentemente a 0 °C a 200 °C, generalmente durante 0,1 horas a 5 dias. La reaccion puede realizarse usando un sistema de reaccion de microondas, debido a que es ventajoso para la suave reaccion en algunos casos. Un disolvente usado para este fin no esta particularmente limitado, en tanto que sea inerte para la reaccion, y ejemplos incluyen hidrocarburos aromaticos (por ejemplo,In this reaction, the compounds (1a) and (2) are used in equal amounts or one of them is used in an excessive amount. A mixture of these compounds is stirred in an inert solvent for the reaction or in the absence of a solvent with reflux cooling conditions, preferably at 0 ° C to 200 ° C, generally for 0.1 hours to 5 days. The reaction can be performed using a microwave reaction system, because it is advantageous for the mild reaction in some cases. A solvent used for this purpose is not particularly limited, as long as it is inert to the reaction, and examples include aromatic hydrocarbons (e.g.,

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benceno, tolueno, xileno), eteres (por ejemplo, eter dietflico, tetrahidrofurano (THF), dioxano, dimetoxietano), hidrocarburos halogenados (por ejemplo, 1,2-dicloroetano, cloroformo), alcoholes (por ejemplo, metanol, etanol, 2- propanol), 1 -metil-2-pirrolidinona (NMP), N,N-dimetilformamida (DMF), N,N-dimetilacetamida (DMA), 1,3-dimetil-2- imidazolidinona (DMI), sulfoxido de dimetilo (DMSO), acetonitrilo, y mezclas de los mismos. La reaccion puede realizarse en presencia de una base organica (por ejemplo, trietilamina, N,N-diisopropiletilamina, N-metilmorfolina, o similares) o una base inorganica (por ejemplo, carbonato de potasio, carbonato sodico, hidroxido potasico, o similares), debido a que es ventajoso para la suave reaccion en algunos casos.benzene, toluene, xylene), ethers (for example, diethyl ether, tetrahydrofuran (THF), dioxane, dimethoxyethane), halogenated hydrocarbons (for example, 1,2-dichloroethane, chloroform), alcohols (for example, methanol, ethanol, 2 - propanol), 1-methyl-2-pyrrolidinone (NMP), N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA), 1,3-dimethyl-2-imidazolidinone (DMI), dimethyl sulfoxide ( DMSO), acetonitrile, and mixtures thereof. The reaction can be carried out in the presence of an organic base (for example, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, or the like) or an inorganic base (for example, potassium carbonate, sodium carbonate, potassium hydroxide, or the like) , because it is advantageous for the smooth reaction in some cases.

Cuando la reaccion se realiza en presencia de una base tal como se muestra anteriormente, dependiendo de las propiedades o similares de los compuestos de partida, la reaccion deseada es imposible o dificil que avance, por ejemplo, debido a la descomposicion o similares de los compuestos de partida. En este caso, la reaccion puede realizarse en presencia de un acido mineral (por ejemplo, acido clorhidrico, acido bromhidrico y similares), un acido organico (por ejemplo, acido acetico, acido propionico y similares) o un acido sulfonico (por ejemplo, acido metanosulfonico, acido p-toluenosulfonico y similares), debido a que es ventajoso para la suave reaccion en algunos casos. Ademas, cuando -LA es alquil inferior-sulfanilo, el atomo de S puede oxidarse con diversos agentes de oxidation tales como Oxone®, acido m-cloroperbenzoico (mCPBA) y acido peracetico para convertir el alquil inferior- sulfanilo en alquil inferior-sulfinilo o alquil inferior-sulfonilo y entonces el alquil inferior-sulfinilo o alquil inferior- sulfonilo puede hacerse reaccionar con el compuesto (2), debido a que es ventajoso para la suave reaccion en algunos casos.When the reaction is carried out in the presence of a base as shown above, depending on the properties or the like of the starting compounds, the desired reaction is impossible or difficult to proceed, for example, due to the decomposition or the like of the compounds. of departure. In this case, the reaction can be carried out in the presence of a mineral acid (for example, hydrochloric acid, hydrobromic acid and the like), an organic acid (for example, acetic acid, propionic acid and the like) or a sulfonic acid (for example, methanesulfonic acid, p-toluenesulfonic acid and the like), because it is advantageous for the mild reaction in some cases. In addition, when -LA is lower alkyl sulfanyl, the atom of S can be oxidized with various oxidation agents such as Oxone®, m-chloroperbenzoic acid (mCPBA) and peracetic acid to convert lower alkyl sulfanyl to lower alkyl sulfinyl or lower alkyl-sulfonyl and then the lower alkyl-sulfinyl or lower alkyl-sulfonyl can be reacted with the compound (2), because it is advantageous for the mild reaction in some cases.

[Documentos][Documents]

S. R. Sandler y W. Karo, “Organic Functional Group Preparations”, segunda edition, vol. 1, Academic Press Inc., 1991S. R. Sandler and W. Karo, "Organic Functional Group Preparations", second edition, vol. 1, Academic Press Inc., 1991

The Chemical Society of Japan, “Fifth Series of Experimental Chemistry,” vol. 14 (2005) (MARUZEN Co., Ltd., Japan)The Chemical Society of Japan, "Fifth Series of Experimental Chemistry," vol. 14 (2005) (MARUZEN Co., Ltd., Japan)

(Proceso de preparation 2)(Preparation process 2)

imagen24image24

(En la formula, -LB representa un grupo saliente, y ejemplos incluyen un halogeno (por ejemplo, F, Cl), un grupo sulfoniloxi (por ejemplo, metanosulfoniloxi, p-toluenosulfoniloxi, trifluorometanosulfoniloxi), alquil inferior-sulfanilo y alquil inferior-sulfonilo)(In the formula, -LB represents a leaving group, and examples include a halogen (for example, F, Cl), a sulfonyloxy group (for example, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy), lower alkyl-sulfanyl and lower alkyl- sulfonyl)

Este proceso pretende preparar el compuesto de la presente invention (I-b) haciendo reaccionar el compuesto (1b) con el compuesto (2).This process is intended to prepare the compound of the present invention (I-b) by reacting the compound (1b) with the compound (2).

En esta reaccion puede aplicarse el procedimiento de Proceso de preparacion 1.In this reaction the procedure of Preparation Process 1 can be applied.

(Smtesis del material de partida 1) (no es parte de la invencion)(Synthesis of starting material 1) (not part of the invention)

imagen25image25

(En la formula, -Lc representa un grupo saliente, y ejemplos incluyen un halogeno (por ejemplo, F, Cl) y un grupo sulfoniloxi (por ejemplo, metanosulfoniloxi, p-toluenosulfoniloxi, trifluorometanosulfoniloxi); RA representa acilo, bencilo, alquilo inferior o -H; y M representa un metal alcalino)(In the formula, -Lc represents a leaving group, and examples include a halogen (for example, F, Cl) and a sulfonyloxy group (for example, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy); RA represents acyl, benzyl, lower alkyl or -H; and M represents an alkali metal)

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Este proceso pretende preparar el compuesto (1a) haciendo reaccionar el compuesto (5), que se obtiene haciendo reaccionar el compuesto (3) con el compuesto (4), con el compuesto (6) y a partir de aqm someter a reaction de desproteccion para eliminar RA.This process is intended to prepare the compound (1a) by reacting the compound (5), which is obtained by reacting the compound (3) with the compound (4), with the compound (6) and from then undergoing a deprotection reaction for remove RA.

En la reaccion que da el compuesto (5) puede aplicarse el procedimiento del Proceso de preparation 1. En la reaccion que da el compuesto (1a) puede aplicarse el procedimiento del Proceso de preparacion 1 y la reaccion puede realizarse usando el compuesto (6) o un reactivo que produce el compuesto (6) en el sistema, y a partir de aqm puede realizarse la reaccion de desproteccion en condiciones de reaccion que estan seleccionadas segun convenga de, por ejemplo, las condiciones de reaccion descritas en Greene y Wuts, “Greene's Protective Groups in Organic Synthesis (cuarta edition, 2007).” Ejemplos del compuesto (6) incluyen acetato sodico y metoxido de sodio. Debe observarse que el compuesto (1a) tambien puede prepararse realizando la reaccion usando una disolucion de peroxido de hidrogeno en lugar del compuesto (6) y a partir de aqm realizando el tratamiento con acido con acido clorhidrico o similares.In the reaction given by the compound (5) the procedure of the Preparation Process 1 can be applied. In the reaction given by the compound (1a) the procedure of the Preparation Process 1 can be applied and the reaction can be performed using the compound (6) or a reagent that produces the compound (6) in the system, and from here the deprotection reaction can be carried out under reaction conditions that are selected as appropriate for, for example, the reaction conditions described in Greene and Wuts, "Greene's Protective Groups in Organic Synthesis (fourth edition, 2007). ”Examples of compound (6) include sodium acetate and sodium methoxide. It should be noted that the compound (1a) can also be prepared by performing the reaction using a solution of hydrogen peroxide in place of the compound (6) and from here by performing the acid treatment with hydrochloric acid or the like.

(Smtesis del material de partida 2)(Synthesis of starting material 2)

[Formula 29][Formula 29]

imagen26image26

(7) (1b)(7) (1b)

Este proceso pretende preparar el compuesto (1b) haciendo reaccionar el compuesto (7) con el compuesto (4).This process is intended to prepare the compound (1b) by reacting the compound (7) with the compound (4).

En esta reaccion puede aplicarse el procedimiento del Proceso de preparacion 1.In this reaction the procedure of Preparation Process 1 can be applied.

El compuesto de formula (I) se aisla y se purifica como compuesto libre o como una sal farmaceuticamente aceptable, hidrato, solvato o sustancia polimorfica cristalina del mismo. Tambien puede prepararse una sal farmaceuticamente aceptable del compuesto de formula (I) sometiendose a reaccion de formation de sal convencional.The compound of formula (I) is isolated and purified as a free compound or as a pharmaceutically acceptable salt, hydrate, solvate or crystalline polymorphic substance thereof. A pharmaceutically acceptable salt of the compound of formula (I) can also be prepared by undergoing conventional salt formation reaction.

El aislamiento y la purification pueden llevarse a cabo aplicando operaciones qmmicas convencionales tales como extraction, cristalizacion fraccionada, diversos tipos de cromatografia por fraccionamiento, etc.The isolation and purification can be carried out by applying conventional chemical operations such as extraction, fractional crystallization, various types of fractionation chromatography, etc.

Pueden prepararse diversos isomeros seleccionando compuestos de partida apropiados o pueden separarse basandose en diferencias en las propiedades fisicas y qmmicas de los isomeros. Por ejemplo, pueden derivarse isomeros opticos en isomeros opticamente puros por tecnicas de resolution optica convencionales (por ejemplo, cristalizacion fraccionada produciendo una sal de diaestereomero con una base o acido opticamente activo, cromatografia sobre una columna quiral o similares, y similares). Tambien pueden prepararse a partir de compuestos de partida opticamente activos apropiados.Various isomers can be prepared by selecting appropriate starting compounds or they can be separated based on differences in the physical and chemical properties of the isomers. For example, optical isomers can be derived in optically pure isomers by conventional optical resolution techniques (for example, fractional crystallization producing a diastereomer salt with an optically active base or acid, chromatography on a chiral column or the like, and the like). They can also be prepared from appropriate optically active starting compounds.

Los compuestos de formula (I) se confirmaron para su actividad farmacologica en las siguientes pruebas. A menos que se especifique de otro modo, los ejemplos de prueba mostrados a continuation pueden llevarse a cabo por un metodo descrito en el documento EP 1914240 o cualquier metodo publicamente conocido y, si se usan reactivos, kits, o similares comercialmente disponibles, pueden llevarse a cabo segun las instrucciones adjuntas a estos productos comercialmente disponibles. Debe observarse que el termino “protema de fusion EML4-ALK v1” se refiere a un polipeptido de la secuencia de aminoacidos representada por SEC ID N°: 2 del Documento de patente 1, y el termino “protema de fusion EML4-ALK v3” se refiere a un polipeptido de la secuencia de aminoacidos representada por SEC ID N°: 130 del Documento de patente 1.The compounds of formula (I) were confirmed for their pharmacological activity in the following tests. Unless otherwise specified, the test examples shown below can be carried out by a method described in EP 1914240 or any publicly known method and, if commercially available reagents, kits, or the like are used, can be carried out. carried out according to the instructions attached to these commercially available products. It should be noted that the term "EML4-ALK v1 fusion protein" refers to a polypeptide of the amino acid sequence represented by SEQ ID NO: 2 of Patent Document 1, and the term "EML4-ALK v3 fusion protein" refers to a polypeptide of the amino acid sequence represented by SEQ ID NO: 130 of Patent Document 1.

Ejemplo de prueba 1: Evaluation de la actividad inhibidora contra la actividad de cinasa de la protema de fusion EML4-ALKTest Example 1: Evaluation of the inhibitory activity against the kinase activity of the EML4-ALK fusion protein

Se creo un retrovirus recombinante a partir del plasmido de expresion FLAG-EML4-ALKv1/pMX-iresCD8 en el que se integro ADNc para la protema de fusion EML4-ALK v1, y se inyecto en celulas BA/F3 de la lmea celular linfoide de raton. Usando un reactivo de perlas magneticas para la separation de celulas y una columna de purificacion (anticuerpo monoclonal anti-CD8 inmovilizado sobre perlas magneticas y una columna de purificacion MiniMACS; ambos son productos de Miltenyi Biotec Inc.), se purificaron celulas que expresaban CD8 de la superficie celular para establecer las celulas BA/F3 que expresan la protema de fusion EML4-ALK v1. A partir de las celulas, la protema de fusion EML4-ALK v1 se purifico y se sometio a evaluacion de la actividad de cinasa. La protema de fusion EML4-ALK v1 se investigo para su actividad de fosforilacion hacia un sustrato de peptido usando un kit de detection de actividad de cinasa (HTRF KinEASE-TK; Cisbio Inc.). Los compuestos de prueba se anadieron cada uno a una disolucion de reaccion que contema la protema enzimatica para dar 8 concentraciones finales de 1000 nMA recombinant retrovirus was created from the expression plasmid FLAG-EML4-ALKv1 / pMX-iresCD8 in which cDNA was integrated for the EML4-ALK v1 fusion protein, and injected into BA / F3 cells of the lymphoid cell line of mouse. Using a magnetic pearl reagent for cell separation and a purification column (anti-CD8 monoclonal antibody immobilized on magnetic beads and a MiniMACS purification column; both are products of Miltenyi Biotec Inc.), cells expressing CD8 from the cell surface to establish the BA / F3 cells that express the EML4-ALK v1 fusion protein. From the cells, the EML4-ALK v1 fusion protein was purified and subjected to kinase activity evaluation. The EML4-ALK v1 fusion protein was investigated for its phosphorylation activity towards a peptide substrate using a kinase activity detection kit (HTRF KinEASE-TK; Cisbio Inc.). The test compounds were each added to a reaction solution containing the enzymatic protein to give 8 final concentrations of 1000 nM

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a 0,3 nM, seguido por la adicion de ATP y reaccion durante 1 hora. La concentracion de ATP usada fue 100 pM. Se preparo otra disolucion de reaccion para contener la protema enzimatica, pero no el compuesto de prueba (en el que el disolvente DMSO solo se anadio al 0,4 % en lugar del compuesto de prueba), seguido de reaccion del mismo modo con o sin adicion de ATP. En ausencia del compuesto de prueba, se supuso que el recuento de fosforilacion sin adicion de ATP y con adicion de ATP era del 100 % de inhibicion y el 0 % de inhibicion, respectivamente. Se calculo la concentracion que causo el 50 % de inhibicion (CI50) para cada compuesto de prueba por el metodo de regresion logfstica.at 0.3 nM, followed by the addition of ATP and reaction for 1 hour. The ATP concentration used was 100 pM. Another reaction solution was prepared to contain the enzyme protein, but not the test compound (in which the DMSO solvent was only added at 0.4% instead of the test compound), followed by the same reaction with or without ATP addition. In the absence of the test compound, the phosphorylation count without ATP addition and with ATP addition was assumed to be 100% inhibition and 0% inhibition, respectively. The concentration that caused 50% inhibition (IC50) for each test compound was calculated by the logistic regression method.

Como resultado, se encontro que algunos compuestos de la presente invencion teman actividad inhibidora contra la actividad de cinasa de la protema de fusion EML4-ALK v1. La Tabla 1 muestra los valores de CI50 obtenidos para algunos compuestos de la presente invencion. Ej indica Ejemplo N°. En la tabla a continuacion, Compuesto X indica una forma racemica del compuesto del Ejemplo 174 mostrado en la publicacion internacional N° WO 2009/136995 (rac-2-{[(1R,2S)-2-aminociclohexil]amino}-4-{[4'-(morfolin-4-il)bifenil-4-il]amino}pirimidin-5-carboxamida) y Compuesto Y indica el compuesto de los Ejemplos 26-22 mostrado en la publicacion internacional N° WO 00/76980 (S-{[2- (dimetilamino)etil]amino}-6-etil-3-[(3-metilfenil)amino]pirazin-2-carboxamida).As a result, some compounds of the present invention were found to have inhibitory activity against the kinase activity of the EML4-ALK v1 fusion protein. Table 1 shows the IC50 values obtained for some compounds of the present invention. Ex indicates Example No. In the table below, Compound X indicates a racemic form of the compound of Example 174 shown in International Publication No. WO 2009/136995 (rac-2 - {[(1R, 2S) -2-aminocyclohexyl] amino} -4- {[4 '- (morpholin-4-yl) biphenyl-4-yl] amino} pyrimidin-5-carboxamide) and Compound Y indicates the compound of Examples 26-22 shown in International Publication No. WO 00/76980 ( S - {[2- (dimethylamino) ethyl] amino} -6-ethyl-3 - [(3-methylphenyl) amino] pyrazin-2-carboxamide).

[Tabla 1] (# no es parte de la invencion)[Table 1] (# is not part of the invention)

Ej  Ex
CI50 (nM) Ej CI50 (nM) Ej CI50 (nM)  IC50 (nM) Ex IC50 (nM) Ex IC50 (nM)

86#  86 #
17 383# 0,23 534 1,0  17 383 # 0.23 534 1.0

110#  110 #
0,99 387 0,26 538 2,3  0.99 387 0.26 538 2.3

284#  284 #
8,9 388 0,17 544 1,9  8.9 388 0.17 544 1.9

325  325
5,3 391 0,22 545 11  5.3 391 0.22 545 11

328#  328 #
76 392 0,21 546 7,8  76 392 0.21 546 7.8

340  340
0,37 399# 0,94 547 1,5  0.37 399 # 0.94 547 1.5

341  341
2,8 406# 0,34 549 2,1  2.8 406 # 0.34 549 2.1

343  343
2,1 426 0,49 550 11  2.1 426 0.49 550 11

347#  347 #
1,7 459 0,26 553 1,4  1.7 459 0.26 553 1.4

354  354
0,77 466 0,93 554 4,5  0.77 466 0.93 554 4.5

355  355
0,33 490 3,1 558 2,2  0.33 490 3.1 558 2.2

357  357
17 491 2,8 Compuesto X 220  17 491 2.8 Compound X 220

370  370
0,65 493 2,6 Compuesto Y >1000  0.65 493 2.6 Compound Y> 1000

377  377
0,24 494 4,1  0.24 494 4.1

378  378
0,26 512 1,5  0.26 512 1.5

Ejemplo de prueba 2: Evaluacion de la actividad inhibidora del crecimiento contra celulas dependientes de la protema de fusion EML4-ALKTest Example 2: Evaluation of growth inhibitory activity against EML4-ALK fusion protein dependent cells

Las celulas BA/F3 que expresan la protema de fusion EML4-ALK v1 pueden cultivarse en ausencia de IL-3. En otras palabras, son celulas que crecen dependientemente de la protema de fusion EML4-ALK v1.BA / F3 cells expressing the EML4-ALK v1 fusion protein can be cultured in the absence of IL-3. In other words, they are cells that grow dependently on the EML4-ALK v1 fusion protein.

En una placa de 96 pocillos (Iwaki), celulas BA/F3 que expresan la protema de fusion EML4-ALK v1 se sembraron a 500 celulas por pocillo en medio RPMI1640 (Invitrogen) que contema 10% de suero bovino fetal, seguido por la adicion de un compuesto de prueba (concentracion final: 10 pM a 0,1 nM). Como control negativo, se anadio DMSO usado como disolvente del compuesto de prueba. Entonces, las celulas se cultivaron bajo 5 % de CO2 a 37 °C durante 2 dfas. Se anadio un reactivo de recuento de celulas (AlmarBlue; Biosource) y las celulas se cultivaron durante 150 minutos, seguido de medicion de la intensidad de fluorescencia con un luminometro (Safire; Tecan) segun las instrucciones adjuntas al reactivo. Suponiendo que el valor medido para el medio solo y el valor medido para el control negativo fueran el 100 % de inhibicion y el 0 % de inhibicion, respectivamente, la tasa de inhibicion se calculo para cada compuesto para asf determinar la concentracion que causa el 50 % de inhibicion (valor de CI50) por el metodo de regresion logfstica.In a 96-well plate (Iwaki), BA / F3 cells expressing EML4-ALK v1 fusion protein were seeded at 500 cells per well in RPMI1640 medium (Invitrogen) containing 10% fetal bovine serum, followed by the addition of a test compound (final concentration: 10 pM at 0.1 nM). As a negative control, DMSO used as solvent of the test compound was added. Then, the cells were grown under 5% CO2 at 37 ° C for 2 days. A cell count reagent (AlmarBlue; Biosource) was added and the cells were cultured for 150 minutes, followed by measurement of the fluorescence intensity with a luminometer (Safire; Tecan) according to the instructions attached to the reagent. Assuming that the value measured for the medium alone and the value measured for the negative control were 100% inhibition and 0% inhibition, respectively, the inhibition rate was calculated for each compound so as to determine the concentration causing the 50 % inhibition (IC50 value) by the logistic regression method.

Como resultado, algunos compuestos de la presente invencion mostraron actividad inhibidora del crecimiento contra celulas BA/F3 que expresaban la protema de fusion EML4-ALK v1. La Tabla 2 muestra los valores de CI50 obtenidos para algunos compuestos de la presente invencion. Ej indica Ejemplo N° En la tabla a continuacion, Compuesto X y Compuesto Y indican respectivamente los compuestos descritos en el Ejemplo de prueba 1.As a result, some compounds of the present invention showed growth inhibitory activity against BA / F3 cells expressing the EML4-ALK v1 fusion protein. Table 2 shows the IC50 values obtained for some compounds of the present invention. Ex indicates Example No. In the table below, Compound X and Compound Y indicate respectively the compounds described in Test Example 1.

[Tabla 2] (# no es parte de la invencion)[Table 2] (# is not part of the invention)

Ej  Ex
CI50 (nM) Ej CI50 (nM) Ej CI50 (nM)  IC50 (nM) Ex IC50 (nM) Ex IC50 (nM)

86#  86 #
68 383# 5,9 534 24  68 383 # 5.9 534 24

110#  110 #
64 387 10 538 7,7  64 387 10 538 7.7

284#  284 #
85 388 4,1 544 27  85 388 4.1 544 27

325  325
20 391 6,5 545 25  20 391 6.5 545 25

328#  328 #
76 392 6,3 546 23  76 392 6.3 546 23

340  340
9,5 399# 11 547 5,7  9.5 399 # 11 547 5.7

341  341
11 406# 9,8 549 14  11 406 # 9.8 549 14

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(continuacion)(continuation)

Ej  Ex
CI50 (nM) Ej CI50 (nM) Ej CI50 (nM)  IC50 (nM) Ex IC50 (nM) Ex IC50 (nM)

343  343
11 426 11 550 39  11 426 11 550 39

347#  347 #
17 459 8,1 553 4,7  17 459 8.1 553 4.7

354  354
8,6 466 9,3 554 14  8.6 466 9.3 554 14

355  355
9,2 490 18 558 16  9.2 490 18 558 16

357  357
60 491 16 Compuesto X 821  60 491 16 Compound X 821

370  370
4,9 493 19 Compuesto Y >1000  4.9 493 19 Compound Y> 1000

377  377
6,9 494 42  6.9 494 42

378  378
6,1 512 19  6.1 512 19

A partir de los resultados de los Ejemplos de prueba 1 y 2 mostrados anteriormente, se confirmo que los compuestos de la presente invencion teman actividad inhibidora contra la actividad de cinasa de la protema de fusion EML4-ALK v1 y actividad inhibidora del crecimiento contra las celulas BA/F3 que expresaban la protema de fusion EML4-ALK v1. Por otra parte, se confirmo que los Compuestos X e Y descritos en el Ejemplo de prueba 1 teman actividad inhibidora extremadamente debil contra la actividad de cinasa de la protema de fusion EML4-ALK v1 y actividad inhibidora del crecimiento contra las celulas BA/F3 que expresan la protema de fusion EML4-ALK v1, en comparacion con los compuestos de la presente invencion.From the results of Test Examples 1 and 2 shown above, it was confirmed that the compounds of the present invention have inhibitory activity against the kinase activity of EML4-ALK v1 fusion protein and growth inhibitory activity against cells BA / F3 expressing the EML4-ALK v1 fusion protein. On the other hand, it was confirmed that Compounds X and Y described in Test Example 1 have extremely weak inhibitory activity against the kinase activity of the EML4-ALK v1 fusion protein and growth inhibitory activity against BA / F3 cells that express the EML4-ALK v1 fusion protein, as compared to the compounds of the present invention.

Ejemplo de prueba 3: Prueba antitumoral (in vivo) sobre celulas dependientes de la protema de fusion EML4-ALKTest Example 3: Antitumor test (in vivo) on EML4-ALK fusion protein dependent cells

Se transfecto el plasmido de expresion EML4-ALKv1/pMXS en el que se integro el ADNc para la protema de fusion EML4-ALK v1 en celulas de fibroblasto 3T3 por el metodo de fosfato calcio para asf establecer las celulas 3T3 que expresaban la protema de fusion EML4-ALK v1. Se inocularon subcutaneamente 3 x 106 celulas de celulas 3T3 que expresaban la protema de fusion EML4-ALK v1 suspensas en PBS mediante inyeccion a la espalda de ratones sin pelo Balb/c macho de 5 semanas de edad (Charles River Japan, Inc.). Despues de 7 dfas de la inoculacion, se inicio la administracion del compuesto de prueba. La prueba se realizo en el grupo de disolvente y el grupo de compuesto, 4 animales por grupo. El compuesto de prueba se suspendio en un disolvente compuesto por 0,5 % de metilcelulosa y se administro por via oral a una dosis de 10 mg/kg. Las administraciones se realizaron una vez al dfa durante 5 dfas, y se midieron el peso corporal y el tamano del tumor cada dos dfas. El volumen del tumor se calculo usando la siguiente formula.The EML4-ALKv1 / pMXS expression plasmid was transfected into which the cDNA for the EML4-ALK v1 fusion protein was integrated into 3T3 fibroblast cells by the calcium phosphate method to establish 3T3 cells expressing the fusion protein EML4-ALK v1. 3 x 106 3T3 cell cells expressing the suspending EML4-ALK v1 fusion protein in PBS were inoculated subcutaneously by injection into the back of 5-week-old male Balb / c hairless mice (Charles River Japan, Inc.). After 7 days of inoculation, administration of the test compound was initiated. The test was carried out in the solvent group and the compound group, 4 animals per group. The test compound was suspended in a solvent composed of 0.5% methylcellulose and administered orally at a dose of 10 mg / kg. The administrations were performed once a day for 5 days, and the body weight and tumor size were measured every two days. Tumor volume was calculated using the following formula.

[Volumen del tumor (mm3)] = [Eje mayor del tumor (mm)] x [eje menor del tumor (mm)]2 x 0,5[Tumor volume (mm3)] = [Major axis of the tumor (mm)] x [minor axis of the tumor (mm)] 2 x 0.5

Suponiendo que el volumen del tumor del grupo de disolvente en el dfa de iniciar y el dfa de terminar la administracion del compuesto de prueba fue el 100% de inhibicion y el 0% de inhibicion, respectivamente, se calculo la tasa de inhibicion del compuesto de prueba. Cuando la regresion del volumen del tumor se induce a partir del dfa de iniciar la administracion, se supusieron que el volumen del tumor en el dfa de iniciar la administracion y el estado en el que el tumor desaparecio eran del 0% de regresion y el 100% de regresion, respectivamente, y se calculo la tasa de regresion del compuesto de prueba.Assuming that the tumor volume of the solvent group on the day of initiation and the day of termination of the administration of the test compound was 100% inhibition and 0% inhibition, respectively, the inhibition rate of the compound was calculated. proof. When the regression of the tumor volume is induced from the day of starting the administration, it was assumed that the volume of the tumor on the day of starting the administration and the state in which the tumor disappeared were 0% regression and 100 Regression%, respectively, and the regression rate of the test compound was calculated.

Como resultado, se confirmo que entre los compuestos de la presente invencion hubo compuestos que inhibieron el crecimiento de tumor de celulas 3T3 que expresan la protema de fusion EML4-ALK v1 y compuestos que indujeron la regresion del tumor de las celulas 3T3 que expresan la protema de fusion EML4-ALK v1. La Tabla 3 muestra la tasa de inhibicion de algunos compuestos de la presente invencion. Debe observarse que en la tabla a continuacion los valores numericos especificados con “(regresion)” indican cada uno una tasa de regresion. Ej indica Ejemplo N°.As a result, it was confirmed that among the compounds of the present invention there were compounds that inhibited tumor growth of 3T3 cells expressing EML4-ALK v1 fusion protein and compounds that induced tumor regression of 3T3 cells expressing the protein EML4-ALK v1. Table 3 shows the inhibition rate of some compounds of the present invention. It should be noted that in the table below the numerical values specified with "(regression)" each indicate a regression rate. Ex indicates Example No.

[Tabla 3][Table 3]

Ej  Ex
(%)  (%)

370  370
81  81

378  378
92  92

392  392
28 (regresion)  28 (regression)

426  426
81  81

466  466
54 (regresion)  54 (regression)

546  546
79  79

549  549
67 (regresion)  67 (regression)

553  553
63  63

558  558
37 (regresion)  37 (regression)

Asf, cuando se administran por via oral, los compuestos de la presente invencion inhibieron el crecimiento tumoral en ratones inoculados con las celulas 3T3 que expresan la protema de fusion EML4-ALK v1 o indujeron la regresion de tumor, confirmando asf que los compuestos de la presente invencion tuvieron actividad oral.Thus, when administered orally, the compounds of the present invention inhibited tumor growth in mice inoculated with 3T3 cells expressing EML4-ALK v1 fusion protein or induced tumor regression, thus confirming that the compounds of the Present invention had oral activity.

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Ejemplo de prueba 4: Prueba antitumoral (in vivo) sobre las celulas dependientes de la protema de fusion EML4-ALKTest Example 4: Antitumor test (in vivo) on EML4-ALK fusion protein dependent cells

Tambien pueden confirmarse los efectos antitumorales sobre las celulas dependientes de la protema de fusion EML4-ALK por el uso de celulas NCI-H2228 de la lmea celular de canceres de pulmon de celulas no pequenas humanos (celulas derivadas de pacientes con cancer de pulmon positivo para polinucleotidos de fusion EML4-ALK (celulas dependientes de la protema de fusion EML4-ALK v3)) en lugar de la protema de fusion EML4-ALK v1 que expresa celulas 3T3 del Ejemplo de prueba 3, como se muestra mas adelante.The antitumor effects on EML4-ALK fusion protein-dependent cells can also be confirmed by the use of NCI-H2228 cells from the lung cell line of human non-small cell lung cancers (cells derived from patients with positive lung cancer for EML4-ALK fusion polynucleotides (EML4-ALK v3 fusion protein dependent cells) instead of the EML4-ALK v1 fusion protein expressing 3T3 cells of Test Example 3, as shown below.

Se inocularon subcutaneamente 3 x 106 celulas de celulas NCI-H2228 suspensas en 50 % de Matrigel (Invitrogen) mediante inyeccion en la espalda de ratones NOD/SCID macho de 5 semanas de edad (Charles River Japan, Inc.). Despues de 3 semanas de la inoculacion, se inicio la administracion de compuestos de prueba. La prueba se realizo en el grupo de disolvente y los grupos de compuesto de prueba, 6 animales por grupo. Los compuestos de prueba se disolvieron cada uno en un disolvente compuesto por 10% de 1 -metil-2-pirrolidinona (SIGMA-ALDRICH Inc.)/90% de polietilenglicol 300 (Fluka Inc.) y se administraron por via oral a una dosis de 1 mg/kg. Las administraciones se realizaron una vez al dfa durante 14 dfas, y se midieron el peso corporal y el tamano del tumor cada dos dfas. Se calculo el volumen del tumor usando la siguiente formula.3 x 106 NCI-H2228 cells suspended in 50% Matrigel (Invitrogen) were inoculated subcutaneously by injection into the back of 5-week-old male NOD / SCID mice (Charles River Japan, Inc.). After 3 weeks of inoculation, the administration of test compounds began. The test was carried out in the solvent group and the test compound groups, 6 animals per group. The test compounds were each dissolved in a solvent composed of 10% 1-methyl-2-pyrrolidinone (SIGMA-ALDRICH Inc.) / 90% polyethylene glycol 300 (Fluka Inc.) and administered orally at a dose of 1 mg / kg. The administrations were performed once a day for 14 days, and the body weight and tumor size were measured every two days. The tumor volume was calculated using the following formula.

[Volumen del tumor (mm3)] = [Eje mayor del tumor (mm)] x [eje menor del tumor (mm)]2 x 0,5[Tumor volume (mm3)] = [Major axis of the tumor (mm)] x [minor axis of the tumor (mm)] 2 x 0.5

Suponiendo que el volumen del tumor del grupo de disolvente en el dfa de iniciar y el dfa de terminar la administracion fue del 100 % de inhibicion y el 0 % de inhibicion, respectivamente, se calculo la tasa de inhibicion para cada compuesto.Assuming that the tumor volume of the solvent group on the day of initiation and the day of termination of administration was 100% inhibition and 0% inhibition, respectively, the inhibition rate for each compound was calculated.

Como resultado, se confirmo que entre los compuestos de la presente invencion hubo compuestos que inhibieron el crecimiento de tumor de celulas NCI-H2228. Por ejemplo, el compuesto del Ejemplo 549 inhibio el crecimiento de tumor de celulas NCI-H2228 el 69 %.As a result, it was confirmed that among the compounds of the present invention there were compounds that inhibited the growth of NCI-H2228 cell tumor. For example, the compound of Example 549 inhibited the growth of NCI-H2228 cell tumor by 69%.

Asf, cuando se administraron por via oral, los compuestos de la presente invencion inhibieron el crecimiento tumoral en ratones inoculados con celulas NCI-H2228 de la lmea celular de cancer de pulmon de celulas no pequenas, confirmando asf que los compuestos de la presente invencion teman actividad oral.Thus, when administered orally, the compounds of the present invention inhibited tumor growth in mice inoculated with NCI-H2228 cells from the non-small cell lung cancer cell line, thus confirming that the compounds of the present invention fear oral activity

Por otra parte, cuando los Compuestos X e Y descritos en el Ejemplo de prueba 1 se administraron, no se mostro inhibicion significativa del crecimiento contra celulas NCI-H2228 (tumor), en comparacion con el grupo de disolvente. La prueba de significancia se realizo por la prueba de la t de Student.On the other hand, when Compounds X and Y described in Test Example 1 were administered, no significant growth inhibition was shown against NCI-H2228 cells (tumor), as compared to the solvent group. The significance test was performed by the Student t test.

En vista de lo anterior, en los Ejemplos de prueba 1 y 2, se confirmo que los compuestos de la presente invencion teman actividad inhibidora contra la actividad de cinasa de la protema de fusion EML4-ALK, ademas de actividad inhibidora del crecimiento contra celulas dependientes de la protema de fusion EML4-ALK. Ademas, en los Ejemplos de prueba 3 y 4 tambien se confirmo que los compuestos de la presente invencion teman un efecto antitumoral sobre celulas dependientes de la protema de fusion EML4-ALK (tumor) basandose en las acciones anteriores. Estos indican que los compuestos de la presente invencion son utiles como principios activos en composiciones farmaceuticas para prevenir y/o tratar cancer, tales como cancer de pulmon en una realizacion, cancer de pulmon de celulas no pequenas o cancer de pulmon de celulas pequenas en otra realizacion, cancer positivo para los polinucleotidos de fusion ALK en otra realizacion mas, cancer de pulmon positivo para los polinucleotidos de fusion ALK en otra realizacion mas, cancer de pulmon de celulas no pequenas positivo para los polinucleotidos de fusion ALK en otra realizacion mas, cancer positivo para protemas de fusion de ALK en otra realizacion mas, cancer de pulmon positivo para protemas de fusion de ALK en otra realizacion mas, cancer de pulmon de celulas no pequenas positivo para protemas de fusion de ALK en otra realizacion mas, cancer positivo para los polinucleotidos de fusion EML4-ALK en otra realizacion mas, cancer de pulmon positivo para los polinucleotidos de fusion EML4-ALK en otra realizacion mas, cancer de pulmon de celulas no pequenas positivo para los polinucleotidos de fusion EML4-ALK en otra realizacion mas, cancer positivo para protemas de fusion EML4-ALK en otra realizacion mas, cancer de pulmon positivo para protemas de fusion EML4-ALK en otra realizacion mas, o cancer de pulmon de celulas no pequenas positivo para protemas de fusion EML4-ALK en otra realizacion mas.In view of the above, in Test Examples 1 and 2, it was confirmed that the compounds of the present invention have inhibitory activity against the kinase activity of the EML4-ALK fusion protein, in addition to growth inhibitory activity against dependent cells of the EML4-ALK fusion protein. Furthermore, in Test Examples 3 and 4 it was also confirmed that the compounds of the present invention have an antitumor effect on cells dependent on the EML4-ALK fusion protein (tumor) based on the above actions. These indicate that the compounds of the present invention are useful as active ingredients in pharmaceutical compositions for preventing and / or treating cancer, such as lung cancer in one embodiment, non-small cell lung cancer or small cell lung cancer in another embodiment, positive cancer for ALK fusion polynucleotides in yet another embodiment, positive lung cancer for ALK fusion polynucleotides in yet another embodiment, non-small cell lung cancer positive for ALK fusion polynucleotides in yet another embodiment, cancer positive for ALK fusion proteins in another embodiment, lung cancer positive for ALK fusion proteins in yet another embodiment, non-small cell lung cancer positive for ALK fusion proteins in another embodiment, positive cancer for EML4-ALK fusion polynucleotides in yet another embodiment, lung cancer positive for EML4-AL fusion polynucleotides K in yet another embodiment, non-small cell lung cancer positive for EML4-ALK fusion polynucleotides in yet another embodiment, positive cancer for EML4-ALK fusion proteins in yet another embodiment, lung cancer positive for EML4 fusion proteins -ALK in another embodiment, or non-small cell lung cancer positive for EML4-ALK fusion proteins in another embodiment.

Hasta la fecha, en cuanto al gen ALK, se han confirmado la presencia de diversos tipos de mutacion puntual activa y expresion en exceso asociados a amplificacion genica en celulas derivadas de pacientes con neuroblastoma (Nature, vol. 455, p. 971, 2008; Cancer Research, vol. 68, p. 3389, 2008). Ademas, se sabe que un compuesto que tiene actividad inhibidora contra la actividad de cinasa de la protema ALK muestra un efecto antitumoral sobre celulas derivadas de pacientes con cancer positivo para los polinucleotidos ALK mutantes y celulas derivadas de pacientes con cancer con expresion en exceso de los polinucleotidos ALK (Cancer Research, vol. 68, p. 3389, 2008). Estos indican que los compuestos de la presente invencion son utiles como principios activos en composiciones farmaceuticas para prevenir y/o tratar neuroblastoma, tales como cancer positivo para los polinucleotidos ALK mutantes en una realizacion, cancer con expresion en exceso de los polinucleotidos ALK en otra realizacion, neuroblastoma positivo para los polinucleotidos ALK mutantes en otra realizacion mas, o neuroblastoma con expresion en exceso de los polinucleotidos ALK en otra realizacion mas.To date, regarding the ALK gene, the presence of various types of active point mutation and excess expression associated with genetic amplification in cells derived from patients with neuroblastoma have been confirmed (Nature, vol. 455, p. 971, 2008; Cancer Research, vol. 68, p. 3389, 2008). In addition, it is known that a compound that has inhibitory activity against the kinase activity of the ALK protein shows an antitumor effect on cells derived from patients with positive cancer for mutant ALK polynucleotides and cells derived from patients with cancer with excess expression of the ALK polynucleotides (Cancer Research, vol. 68, p. 3389, 2008). These indicate that the compounds of the present invention are useful as active ingredients in pharmaceutical compositions for preventing and / or treating neuroblastoma, such as positive cancer for mutant ALK polynucleotides in one embodiment, cancer with excess expression of ALK polynucleotides in another embodiment. , neuroblastoma positive for mutant ALK polynucleotides in another embodiment, or neuroblastoma with excess expression of ALK polynucleotides in yet another embodiment.

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Los compuestos de formula (I) tambien se confirmaron para su actividad farmacologica en las siguientes pruebas. A menos que se especifique de otro modo, los ejemplos de prueba mostrados a continuacion pueden llevarse a cabo de una manera conocida y, si se usan reactivos y/o kits comercialmente disponibles, pueden llevarse a cabo segun las instrucciones adjuntas a estos productos comercialmente disponibles.The compounds of formula (I) were also confirmed for their pharmacological activity in the following tests. Unless otherwise specified, the test examples shown below can be carried out in a known manner and, if commercially available reagents and / or kits are used, they can be carried out according to the instructions attached to these commercially available products. .

Ejemplo de prueba 5: Evaluacion de la actividad inhibidora contra la actividad de cinasa de la protema RETTest Example 5: Evaluation of the inhibitory activity against the kinase activity of the RET protein

Se compro una protema parcial de solo un dominio de cinasa de la protema RET de Carna Biosciences Inc., Japon. Se investigo la actividad de fosforilacion hacia un sustrato de peptido usando un lector EZ (Caliper). Los compuestos de prueba se mezclaron cada uno con una disolucion de protema para dar 8 concentraciones finales de 100 nM a 0,03 nM, seguido por la adicion de un lfquido mixto de ATP y peptido de sustrato (Caliper) y reaccion durante 30 minutos. La concentracion de ATP usada fue 100 pM. Se preparo un lfquido de reaccion que contema protema, pero no compuesto de prueba (en el que el disolvente DMSO solo se anadio al 0,8 % en lugar del compuesto de prueba), seguido de reaccion del mismo modo con o sin adicion de ATP. En ausencia del compuesto de prueba, se supuso que el pico del peptido de fosforilacion sin adicion de ATP y con adicion de ATP era del 100 % de inhibicion y del 0 % de inhibicion, respectivamente. La concentracion del compuesto de prueba que causo el 50 % de inhibicion (valor de CI50) se calculo por el metodo de regresion logfstica.A partial protein was purchased from only one kinase domain of the RET protein from Carna Biosciences Inc., Japan. Phosphorylation activity was investigated towards a peptide substrate using an EZ reader (Caliper). The test compounds were each mixed with a protein solution to give 8 final concentrations of 100 nM to 0.03 nM, followed by the addition of a mixed ATP liquid and substrate peptide (Caliper) and reaction for 30 minutes. The ATP concentration used was 100 pM. A reaction liquid containing protection but not test compound was prepared (in which the DMSO solvent was only added at 0.8% instead of the test compound), followed by reaction in the same way with or without the addition of ATP . In the absence of the test compound, it was assumed that the peak of the phosphorylation peptide without the addition of ATP and with the addition of ATP was 100% inhibition and 0% inhibition, respectively. The concentration of the test compound that caused 50% inhibition (IC50 value) was calculated by the logistic regression method.

Como resultado, algunos compuestos de la presente invencion mostraron actividad inhibidora contra la actividad de cinasa de la protema RET. La Tabla 4 muestra los valores de CI50 obtenidos para algunos compuestos de la presente invencion. Ej indica Ejemplo N°.As a result, some compounds of the present invention showed inhibitory activity against the kinase activity of the RET protein. Table 4 shows the IC50 values obtained for some compounds of the present invention. Ex indicates Example No.

[Tabla 41[Table 41

Ej  Ex
CI50 (nM) Ej CI50 (nM) Ej CI50 (nM)  IC50 (nM) Ex IC50 (nM) Ex IC50 (nM)

565  565
1,1 571 1,1 577 3,4  1.1 571 1.1 577 3.4

566  566
0,95 572 1,3 578 1,5  0.95 572 1.3 578 1.5

567  567
1,7 573 1,0 579 1,1  1.7 573 1.0 579 1.1

568  568
1,5 574 1,0 580 3,6  1.5 574 1.0 580 3.6

569  569
1,0 575 1,3 581 2,9  1.0 575 1.3 581 2.9

570  570
2,3 576 1,3 582 1,1  2.3 576 1.3 582 1.1

RET (reorganizado durante la transfeccion) es una tirosina cinasa de receptor y es una protema que tiene una region transmembranaria en la parte central, flanqueada por una region de tirosina cinasa en el lado del extremo carboxilo y una region extracelular en el lado del extremo amino.RET (rearranged during transfection) is a receptor tyrosine kinase and is a protein that has a transmembrane region in the central part, flanked by a region of tyrosine kinase on the side of the carboxyl end and an extracellular region on the side of the amino end .

A partir de los resultados del Ejemplo de prueba 5, se confirmo que los compuestos de la presente invencion teman actividad inhibidora contra la actividad de cinasa de la protema RET. Hasta la fecha, en cuanto al gen RET, se ha confirmado mutacion puntual activa en celulas o espedmenes de tejido de cancer derivados de canceres de pulmon de celulas no pequenas, cancer de pulmon de celulas pequenas, cancer de tiroides, feocromocitoma adrenal, cancer de colon y cancer pancreatico, y la fusion con genes H4, H4L, PRKAR1A, NCOA4, GOLGA5, HTIF1, TIF1G, TKTN1, RFG9, ELKS, PCM1, RFP y HOOK3 se ha confirmado en celulas o espedmenes de tejido de cancer derivados de cancer de tiroides, cancer de ovario y mesotelioma (mutacion puntual en cancer de pulmon de celulas no pequenas: Nature Genetics, 2007, 39, 347-351; mutacion puntual en cancer de pulmon de celulas pequenas: Japanese Journal of Cancer Research, 1995, 86, 1127-1130; fusion y mutacion puntual en cancer de tiroides: Endocrine Reviews, 2006, 27, 535-560; mutacion puntual en tumor adrenal: Journal of Clinical Endocrinology and Metabolism, 1996, 81, 2041-2046; mutacion puntual en cancer de colon: Science, 2006, 314, 268-274; mutacion puntual en cancer pancreatico: Cancer Research, 2005, 65, 11536-11544; fusion en cancer de ovario: International Journal of Surgical Pathology, 2009, 17, 107-110; fusion en mesotelioma: Cancer letters, 2008, 265, 55-66). Ademas, se sabe que un compuesto que tiene actividad inhibidora contra la actividad de cinasa de la protema RET muestra un efecto antitumoral sobre celulas derivadas de pacientes con cancer positivo para los polinucleotidos RET mutantes y celulas derivadas de pacientes con cancer positivos para los polinucleotidos de fusion RET (Endocrine Reviews, 2006, 27, 535-560). Estos indican que los compuestos de la presente invencion son utiles como principios activos en composiciones farmaceuticas para prevenir y/o tratar cancer de tiroides, tal como feocromocitoma adrenal en una realizacion, cancer de colon en otra realizacion, cancer pancreatico en otra realizacion mas, cancer de ovario en otra realizacion mas, mesotelioma en otra realizacion mas, cancer positivo para los polinucleotidos RET mutantes en otra realizacion mas, cancer de pulmon positivo para los polinucleotidos RET mutantes en otra realizacion mas, cancer de pulmon de celulas no pequenas positivo para los polinucleotidos RET mutantes en otra realizacion mas, cancer de pulmon de celulas pequenas positivo para los polinucleotidos RET mutantes en otra realizacion mas, cancer de tiroides positivo para los polinucleotidos RET mutantes en otra realizacion mas, feocromocitoma adrenal positivo para los polinucleotidos RET mutantes en otra realizacion mas, cancer de colon positivo para los polinucleotidos RET mutantes en otra realizacion mas, cancer pancreatico positivo para los polinucleotidos RET mutantes en otra realizacion mas, cancer positivo para los polinucleotidos de fusion RET en otra realizacion mas, cancer de tiroides positivo para los polinucleotidos de fusion RET en otra realizacion mas, cancer de ovario positivo para los polinucleotidos de fusion RET en otra realizacion mas, o mesotelioma positivo para los polinucleotidos de fusion RET en otra realizacion mas.From the results of Test Example 5, it was confirmed that the compounds of the present invention have inhibitory activity against the kinase activity of the RET protein. To date, as regards the RET gene, active point mutation has been confirmed in cancer cells or tissue tissues derived from non-small cell lung cancers, small cell lung cancer, thyroid cancer, adrenal pheochromocytoma, cancer of colon and pancreatic cancer, and fusion with H4, H4L, PRKAR1A, NCOA4, GOLGA5, HTIF1, TIF1G, TKTN1, RFG9, ELKS, PCM1, RFP and HOOK3 genes has been confirmed in cancer tissue cells or cancer-derived skin tumors Thyroid, ovarian cancer and mesothelioma (punctual mutation in non-small cell lung cancer: Nature Genetics, 2007, 39, 347-351; punctual mutation in small cell lung cancer: Japanese Journal of Cancer Research, 1995, 86, 1127-1130; fusion and point mutation in thyroid cancer: Endocrine Reviews, 2006, 27, 535-560; point mutation in adrenal tumor: Journal of Clinical Endocrinology and Metabolism, 1996, 81, 2041-2046; point mutation in cancer of colon: Science, 2006, 314, 268-27 4; point mutation in pancreatic cancer: Cancer Research, 2005, 65, 11536-11544; fusion in ovarian cancer: International Journal of Surgical Pathology, 2009, 17, 107-110; fusion in mesothelioma: Cancer letters, 2008, 265, 55-66). In addition, it is known that a compound having inhibitory activity against the kinase activity of the RET protein shows an antitumor effect on cells derived from patients with positive cancer for mutant RET polynucleotides and cells derived from patients with cancer positive for fusion polynucleotides RET (Endocrine Reviews, 2006, 27, 535-560). These indicate that the compounds of the present invention are useful as active ingredients in pharmaceutical compositions for preventing and / or treating thyroid cancer, such as adrenal pheochromocytoma in one embodiment, colon cancer in another embodiment, pancreatic cancer in another embodiment, cancer of ovary in yet another embodiment, mesothelioma in yet another embodiment, positive cancer for mutant RET polynucleotides in another embodiment, lung cancer positive for mutant RET polynucleotides in yet another embodiment, non-small cell lung cancer positive for polynucleotides RET mutants in yet another embodiment, small cell lung cancer positive for the mutant RET polynucleotides in yet another embodiment, positive thyroid cancer for the mutant RET polynucleotides in yet another embodiment, positive adrenal pheochromocytoma for mutant RET polynucleotides in yet another embodiment , polynucleus positive colon cancer mutant RET tidos in yet another embodiment, positive pancreatic cancer for mutant RET polynucleotides in yet another embodiment, positive cancer for RET fusion polynucleotides in yet another embodiment, positive thyroid cancer for RET fusion polynucleotides in yet another embodiment, cancer of positive ovary for RET fusion polynucleotides in yet another embodiment, or positive mesothelioma for RET fusion polynucleotides in yet another embodiment.

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Ejemplo de prueba 6: Evaluacion de la actividad inhibidora contra la actividad de cinasa de la protema ROSTest Example 6: Evaluation of the inhibitory activity against the kinase activity of the ROS protein

Se compro una protema parcial de solo un dominio de cinasa de la protema ROS de Carna Biosciences Inc., Japon, y se realizaron pruebas como en Ejemplo de prueba 5, excepto que la concentracion de ATP en la disolucion mixta de ATP y peptido de sustrato (Compas calibrador) fue 50 uM.A partial protein of only one kinase domain of the ROS protein from Carna Biosciences Inc., Japan was purchased and tests were performed as in Test Example 5, except that the concentration of ATP in the mixed solution of ATP and substrate peptide (Compass calibrator) was 50 uM.

Como resultado, algunos compuestos de la presente invencion mostraron actividad inhibidora contra la actividad de la cinasa de protema ROS. La Tabla 5 muestra los valores de CI50 obtenidos para algunos compuestos de la presente invencion. Ej indica Ejemplo N°.As a result, some compounds of the present invention showed inhibitory activity against the activity of the ROS protein kinase. Table 5 shows the IC50 values obtained for some compounds of the present invention. Ex indicates Example No.

[Tabla 51[Table 51

Ej  Ex
CI50 (nM) Ej CI50 (nM) Ej CI50 (nM)  IC50 (nM) Ex IC50 (nM) Ex IC50 (nM)

565  565
0,40 571 0,86 577 1,9  0.40 571 0.86 577 1.9

566  566
0,86 572 0,37 578 0,51  0.86 572 0.37 578 0.51

567  567
0,23 573 0,78 579 0,58  0.23 573 0.78 579 0.58

568  568
1,0 574 1,3 580 0,29  1.0 574 1.3 580 0.29

569  569
0,65 575 1,6 581 0,41  0.65 575 1.6 581 0.41

570  570
0,51 576 1,9 582 1,2  0.51 576 1.9 582 1.2

ROS (homologo 1 del oncogen del virus del sarcoma UR2 aviar de v-Ros) es una tirosina cinasa de receptor y es una protema que tiene una region transmembranaria en la parte central, flanqueada por una region de tirosina cinasa en el lado del extremo carboxilo y una region estructural en el lado del extremo amino.ROS (v-Ros avian UR2 sarcoma virus oncogene homologue 1) is a receptor tyrosine kinase and is a protein that has a transmembrane region in the central part, flanked by a region of tyrosine kinase on the carboxyl end side and a structural region on the amino end side.

A partir de los resultados del Ejemplo de prueba 6, se confirmo que los compuestos de la presente invencion teman actividad inhibidora contra la actividad de cinasa de la protema ROS. Hasta la fecha, en cuanto al gen ROS, la fusion con el gen FIG, el gen SLC34A2 y el gen CD74 se ha confirmado en celulas o espedmenes de tejido de cancer derivados de canceres de pulmon de celulas no pequenas y glioblastoma (Biochimica et Biophysica Acta (BBA) Reviews on Cancer, 2009, 1795, 37-52). Ademas, como se sabe que el ARNip que inhibe la expresion de moleculas de lmeas celulares derivadas de pacientes con cancer positivo para los polinucleotidos de fusion SLC34A2-ROS muestra un efecto antitumoral sobre las lmeas celulares (Cell, 2007, 131, 1190-1203), puede esperarse que un compuesto que tiene actividad inhibidora contra la actividad de cinasa de la protema ROS muestre un efecto antitumoral sobre el cancer positivo para los polinucleotidos de fusion ROS. Estos indican que los compuestos de la presente invencion son utiles como principios activos en composiciones farmaceuticas para prevenir y/o tratar glioblastoma, tales como cancer positivo para los polinucleotidos de fusion ROS en una realizacion, cancer de pulmon positivo para los polinucleotidos de fusion ROS en otra realizacion, cancer de pulmon de celulas no pequenas positivo para los polinucleotidos de fusion ROS en otra realizacion mas, o glioblastoma positivo para los polinucleotidos de fusion ROS en otra realizacion mas.From the results of Test Example 6, it was confirmed that the compounds of the present invention have inhibitory activity against the kinase activity of the ROS protein. To date, as regards the ROS gene, the fusion with the FIG gene, the SLC34A2 gene and the CD74 gene has been confirmed in cancer tissue cells or tissue derived from non-small cell lung cancers and glioblastoma (Biochimica et Biophysica Minutes (BBA) Reviews on Cancer, 2009, 1795, 37-52). In addition, it is known that the siRNA that inhibits the expression of cell line molecules derived from patients with positive cancer for SLC34A2-ROS fusion polynucleotides shows an antitumor effect on cell lines (Cell, 2007, 131, 1190-1203) , a compound having inhibitory activity against the kinase activity of the ROS protein can be expected to show an antitumor effect on cancer positive for ROS fusion polynucleotides. These indicate that the compounds of the present invention are useful as active ingredients in pharmaceutical compositions for preventing and / or treating glioblastoma, such as positive cancer for ROS fusion polynucleotides in one embodiment, positive lung cancer for ROS fusion polynucleotides in another embodiment, non-small cell lung cancer positive for ROS fusion polynucleotides in yet another embodiment, or positive glioblastoma for ROS fusion polynucleotides in yet another embodiment.

Ejemplo de prueba 7: Evaluacion de la actividad inhibidora contra la actividad de cinasa de la protema FLT3Test Example 7: Evaluation of the inhibitory activity against the kinase activity of the FLT3 protein

Se compro una protema parcial de solo un dominio de cinasa de la protema FLT3 de Carna Biosciences Inc., Japon, y se realizaron pruebas como en el Ejemplo de prueba 5.A partial protein of only one kinase domain of the FLT3 protein from Carna Biosciences Inc., Japan was purchased and tests were performed as in Test Example 5.

Como resultado, algunos compuestos de la presente invencion mostraron actividad inhibidora contra la actividad de cinasa de la protema FLT3. La Tabla 6 muestra los valores de CI50 obtenidos para algunos compuestos de la presente invencion. Ej indica ejemplo N°.As a result, some compounds of the present invention showed inhibitory activity against the kinase activity of the FLT3 protein. Table 6 shows the IC50 values obtained for some compounds of the present invention. Ex indicates example No.

[Tabla 61[Table 61

Ej  Ex
CI50 (nM) Ej CI50 (nM) Ej CI50 (nM)  IC50 (nM) Ex IC50 (nM) Ex IC50 (nM)

565  565
0,44 571 0,39 577 0,41  0.44 571 0.39 577 0.41

566  566
0,51 572 0,34 578 0,56  0.51 572 0.34 578 0.56

567  567
0,46 573 0,37 579 0,36  0.46 573 0.37 579 0.36

568  568
0,50 574 0,36 580 0,4,9  0.50 574 0.36 580 0.4.9

569  569
0,35 575 0,72 581 0,52  0.35 575 0.72 581 0.52

570  570
0,66 576 0,51 582 0,37  0.66 576 0.51 582 0.37

FLT3 (tirosina cinasa 3 similar a Fms) es una tirosina cinasa de receptor y es una protema que tiene una region transmembranaria en la parte central, flanqueada por una region de tirosina cinasa en el lado del extremo carboxilo y una region estructural en el lado del extremo amino.FLT3 (tyrosine kinase 3 similar to Fms) is a receptor tyrosine kinase and is a protein that has a transmembrane region in the central part, flanked by a region of tyrosine kinase on the side of the carboxyl end and a structural region on the side of the amino end.

A partir de los resultados del Ejemplo de prueba 7, se confirmo que los compuestos de la presente invencion teman actividad inhibidora contra la actividad de cinasa de la protema FLT3. Hasta la fecha, en cuanto al gen FLT3, se habfan confirmado mutacion puntual activa y mutacion de duplicacion en tandem interna en la region de yuxtamembrana (FLT3-ITD) en celulas derivadas de pacientes con leucemia mielocftica aguda, y se ha confirmado la fusion con el gen SPTBN1 en celulas derivadas de pacientes con leucemia mielocftica cronica aftpica (mutacionFrom the results of Test Example 7, it was confirmed that the compounds of the present invention have inhibitory activity against the kinase activity of the FLT3 protein. To date, as regards the FLT3 gene, active point mutation and internal tandem duplication mutation in the juxtamembrane region (FLT3-ITD) in cells derived from patients with acute myelocytic leukemia have been confirmed, and fusion has been confirmed with the SPTBN1 gene in cells derived from patients with chronic chronic myelocytic leukemia (mutation

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puntual activa y duplicacion en tandem interna en la region de yuxtamembrana en leucemia mielocftica aguda: Current Pharmaceutical Design, 2005, 11, 3449-3457; fusion en leucemia mielocftica cronica atipica: Experimental Hematology, 2007, 35, 1723-1727). Ademas, se sabe que un compuesto que tiene actividad inhibidora contra la actividad de cinasa de la protema FLT3 muestra un efecto antitumoral sobre celulas derivadas de pacientes con cancer positivo para los polinucleotidos FLT3 mutantes y celulas derivadas de pacientes con cancer positivo para los polinucleotidos de fusion SPTBN1-FLT3 (Current Pharmaceutical Design, 2005, 11, 3449-3457; Experimental Hematology, 2007, 35, 1723-1727). Estos indican que los compuestos de la presente invencion son utiles como principios activos en composiciones farmaceuticas para prevenir y/o tratar leucemia mielocftica aguda, tales como pacientes con leucemia mielocftica cronica atfpica en una realizacion, cancer positivo para los polinucleotidos FLT3 mutantes en otra realizacion, leucemia mielocftica aguda mutante positivo para los polinucleotidos FLT3 en otra realizacion mas, cancer positivo para los polinucleotidos de fusion FLT3 en otra realizacion mas, o leucemia mielocftica cronica atfpica positiva para los polinucleotidos de fusion FLT3 en otra realizacion mas.active point and internal tandem duplication in the juxtamembrane region in acute myelocytic leukemia: Current Pharmaceutical Design, 2005, 11, 3449-3457; fusion in atypical chronic myelocytic leukemia: Experimental Hematology, 2007, 35, 1723-1727). Furthermore, it is known that a compound that has inhibitory activity against the kinase activity of the FLT3 protein shows an antitumor effect on cells derived from patients with positive cancer for mutant FLT3 polynucleotides and cells derived from patients with positive cancer for fusion polynucleotides SPTBN1-FLT3 (Current Pharmaceutical Design, 2005, 11, 3449-3457; Experimental Hematology, 2007, 35, 1723-1727). These indicate that the compounds of the present invention are useful as active ingredients in pharmaceutical compositions for preventing and / or treating acute myelocytic leukemia, such as patients with atypical chronic myelocytic leukemia in one embodiment, positive cancer for mutant FLT3 polynucleotides in another embodiment, acute mutant myelocytic leukemia positive for FLT3 polynucleotides in yet another embodiment, positive cancer for FLT3 fusion polynucleotides in yet another embodiment, or positive atypical chronic myelocytic leukemia for FLT3 fusion polynucleotides in yet another embodiment.

Ejemplo de prueba 8: Perfilado de la inhibicion de cinasasTest Example 8: Kinase Inhibition Profiling

Se calcularon las tasas de inhibicion contra 78 tipos de tirosina cinasas (ABL, ARG, BTK, BMX, ITK, TEC, TXK, FRK, BLK, LCK, HCK, LYN, FGR, FYN, SRC, YES, BRK, SRM, CSK, CTK, FER, FES, ACK, TNK1, HER4, EGFR, HER2, JAK1, TYK2, JAK2, JAK3, ROS, ALK, LTK, IRR, INSR, IGF1R, DDR1, DDR2, MUSK, TRKA, TRKB, TRKC, TYRO3, AXL, MER, MET, RON, RET, FGFR4, FGFR1, FGFR2, FGFR3, FLT4, KDR, FLT1, FLT3, FMS, KIT, PDGFRa, PDGFRb, TIE2, EphA1, EphA2, EphA8, EphA7, EphA6, EphA4, EphA3, EphA5, EphB4, EphB3, EphB1 EphB2, FAK, PYK2, SYK, ZAP70) para cada compuesto de prueba a 5 nM. La medicion de la actividad se hizo por Carna Biosciences Inc., Japon, y los datos se analizaron del siguiente modo: suponiendo que la senal promedio de los pocillos de control que conternan todos los componentes de reaccion era del 0 % de inhibicion y la senal promedio en ausencia de la enzima era del 100 % de inhibicion, la tasa de inhibicion se calculo para cada sustancia de prueba a partir de la senal promedio de dos pocillos de prueba.Inhibition rates were calculated against 78 types of tyrosine kinases (ABL, ARG, BTK, BMX, ITK, TEC, TXK, FRK, BLK, LCK, HCK, LYN, FGR, FYN, SRC, YES, BRK, SRM, CSK , CTK, FER, FES, ACK, TNK1, HER4, EGFR, HER2, JAK1, TYK2, JAK2, JAK3, ROS, ALK, LTK, IRR, INSR, IGF1R, DDR1, DDR2, MUSK, TRKA, TRKB, TRKC, TYRO3 , AXL, MER, MET, RON, RET, FGFR4, FGFR1, FGFR2, FGFR3, FLT4, KDR, FLT1, FLT3, FMS, KIT, PDGFRa, PDGFRb, TIE2, EphA1, EphA2, EphA8, EphA7, EphA6, EphAph, Eph4, EphA3 , EphA5, EphB4, EphB3, EphB1 EphB2, FAK, PYK2, SYK, ZAP70) for each test compound at 5 nM. The measurement of the activity was made by Carna Biosciences Inc., Japan, and the data were analyzed as follows: assuming that the average signal of the control wells that conternating all the reaction components was 0% inhibition and the signal average in the absence of the enzyme was 100% inhibition, the inhibition rate was calculated for each test substance from the average signal of two test wells.

Como resultado, a una concentracion de 5 nM, algunos compuestos de la presente invencion mostraron el 50 % o mas de actividad inhibidora contra 7 tipos de cinasas que incluyen ALK, RET, ROS y FLT3 y, por tanto, parecen ser altamente selectivos para cinasas espedficas y tener menos miedos sobre seguridad, miedos que se inducen por la inhibicion de cinasas no diana responsables de efectos secundarios.As a result, at a concentration of 5 nM, some compounds of the present invention showed 50% or more inhibitory activity against 7 types of kinases that include ALK, RET, ROS and FLT3 and therefore appear to be highly selective for kinases. specific and have less fears about safety, fears that are induced by the inhibition of non-target kinases responsible for side effects.

Una composicion farmaceutica que comprende uno o mas compuestos de formula (I) o sales farmaceuticamente aceptables de los mismos como principio activo puede prepararse de un modo convencional usando un excipiente farmaceutico, un vetftculo farmaceutico u otros aditivos comunmente usados en la materia.A pharmaceutical composition comprising one or more compounds of formula (I) or pharmaceutically acceptable salts thereof as active ingredient can be prepared in a conventional manner using a pharmaceutical excipient, a pharmaceutical carrier or other additives commonly used in the art.

Cualquier modo de administracion puede usarse, tanto administracion por via oral en la forma de dosificacion de comprimidos, pftdoras, capsulas, granulos, polvos, disoluciones o similares, como administracion parenteral en la forma de dosificacion de inyecciones (por ejemplo, intrarticular, intravenosa, intramuscular y similares), supositorios, colirios, pomadas oculares, disoluciones percutaneas, pomadas, parches percutaneos, disoluciones transmucosales, parches transmucosales, inhalantes o similares.Any mode of administration can be used, both orally in the dosage form of tablets, pills, capsules, granules, powders, solutions or the like, as parenteral administration in the form of injection dosages (e.g., intra-articular, intravenous, intramuscular and the like), suppositories, eye drops, eye ointments, percutaneous solutions, ointments, percutaneous patches, transmucosal solutions, transmucosal patches, inhalants or the like.

Las composiciones solidas usadas para administracion por via oral incluyen comprimidos, polvos, granulos y similares. En estas composiciones solidas, uno o mas principios activos se mezclan con al menos un excipiente inerte, por ejemplo, lactosa, manitol, glucosa, hidroxipropilcelulosa, celulosa microcristalina, almidon, polivinilpirrolidona y/o aluminometasilicato de magnesio, o similares. Las composiciones tambien pueden comprender aditivos inertes, por ejemplo, lubricantes (por ejemplo, estearato de magnesio y similares), agentes disgregantes (por ejemplo, carboximetilalmidon sodico y similares), estabilizadores y/o solubilizantes, como en los casos usuales. Los comprimidos o pftdoras pueden recubrirse con recubrimiento de azucar o una peftcula gastrica o enterica, si fuera necesario.Solid compositions used for oral administration include tablets, powders, granules and the like. In these solid compositions, one or more active ingredients are mixed with at least one inert excipient, for example, lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone and / or magnesium aluminometasilicate, or the like. The compositions may also comprise inert additives, for example, lubricants (for example, magnesium stearate and the like), disintegrating agents (for example, sodium carboxymethyl starch and the like), stabilizers and / or solubilizers, as in the usual cases. The tablets or pills can be coated with sugar coating or a gastric or enteric film, if necessary.

Las composiciones ftquidas para administracion por via oral incluyen emulsiones farmaceuticamente aceptables, disoluciones, suspensiones, jarabes, elixires, o similares, y comprenden diluyentes inertes comunmente usados tales como agua purificada o etanol. Estas composiciones ftquidas pueden comprender, ademas de diluyentes inertes, auxiliares (por ejemplo, solubilizantes, agentes humectantes, agentes de suspension y similares), edulcorantes, aromas, aromaticos y/o antisepticos.Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, or the like, and comprise commonly used inert diluents such as purified water or ethanol. These liquid compositions may comprise, in addition to inert, auxiliary diluents (for example, solubilizers, wetting agents, suspending agents and the like), sweeteners, aromas, aromatics and / or antiseptics.

Las inyecciones para administracion parenteral incluyen disoluciones, suspensiones o emulsiones acuosas o no acuosas esteriles. Ejemplos de disolventes acuosos incluyen agua destilada inyectable o solucion salina fisiologica. Ejemplos de disolventes no acuosos incluyen propilenglicol, polietilenglicol o aceites vegetales (por ejemplo, aceite de oliva y similares), ademas de alcoholes (por ejemplo, etanol y similares) o Polisorbato 80 (nombre de la farmacopea), y similares. Estas composiciones pueden comprender ademas agentes isotonizantes, antisepticos, agentes humectantes, emulsionantes, dispersantes, estabilizadores o solubilizantes. Se esterilizan, por ejemplo, por filtracion a traves de un filtro de retencion de bacterias, por incorporacion con desinfectantes o por irradiacion. Alternativamente, pueden formularse en una composicion solida esteril y reconstituirse para su uso siendo disueltos o suspensos en agua esteril o un disolvente inyectable esteril antes de uso.Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions or emulsions. Examples of aqueous solvents include injectable distilled water or physiological saline. Examples of non-aqueous solvents include propylene glycol, polyethylene glycol or vegetable oils (for example, olive oil and the like), in addition to alcohols (for example, ethanol and the like) or Polysorbate 80 (name of the pharmacopoeia), and the like. These compositions may also comprise isotonic, antiseptic, wetting, emulsifying, dispersing, stabilizing or solubilizing agents. They are sterilized, for example, by filtration through a bacteria retention filter, by incorporation with disinfectants or by irradiation. Alternatively, they can be formulated in a solid sterile composition and reconstituted for use by being dissolved or suspended in sterile water or a sterile injectable solvent before use.

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Formulaciones para uso externo incluyen pomadas, apositos, cremas, gelatinas, cataplasmas, esprays, lociones, colirios, pomadas oculares y similares. Comprenden bases de pomada comunmente usadas, bases de locion, disoluciones acuosas o no acuosas, suspensiones, emulsiones o similares. Ejemplos de bases de pomada o de locion incluyen polietilenglicol, propilenglicol, vaselina filante, cera de abeja blanca, aceite de ricino hidrogenado con polioxietileno, monoestearato de glicerina, alcohol esteanlico, alcohol cetilico, Lauromacrogol, sesquioleato de sorbitano y similares.Formulations for external use include ointments, dressings, creams, jellies, poultices, sprays, lotions, eye drops, eye ointments and the like. They comprise commonly used ointment bases, lotion bases, aqueous or non-aqueous solutions, suspensions, emulsions or the like. Examples of ointment bases or lotions include polyethylene glycol, propylene glycol, petrolatum, white beeswax, castor oil hydrogenated with polyoxyethylene, glycerol monostearate, steanolic alcohol, cetyl alcohol, Lauromacrogol, sorbitan sesquioleate and the like.

Formulaciones transmucosa tales como inhalantes o formulaciones transnasales se usan en forma solida, lfquida o semi-solida y pueden prepararse de una manera convencionalmente conocida. Por ejemplo, tales formulaciones pueden complementarse segun convenga con excipientes conocidos y adicionalmente con ajustadores del pH, antisepticos, tensioactivos, lubricantes, estabilizadores, espesantes, etc. Para su administracion puede usarse un dispositivo apropiado para inhalacion o insuflacion. Por ejemplo, usando un dispositivo conocido (por ejemplo, un dispositivo de inhalacion de dosis medida y similares) o un nebulizador, el (los) compuesto(s) puede(n) administrarse solos o como un polvo de una mezcla formulada o como una disolucion o suspension en combinacion con un vehfculo farmaceuticamente aceptable. Inhaladores de polvo seco o similares puede ser para uso de administracion unica o multiple, y pueden usarse polvos secos o capsulas que contienen polvo en tales dispositivos. Alternativamente, pueden estar en forma de esprays presurizados con aerosol o similares que usan un propulsor apropiado, por ejemplo, un gas preferido tal como clorofluoroalcano, hidrofluoroalcano, dioxido de carbono, o similares.Transmucosal formulations such as inhalants or transnasal formulations are used in solid, liquid or semi-solid form and can be prepared in a conventionally known manner. For example, such formulations can be supplemented as appropriate with known excipients and additionally with pH adjusters, antiseptics, surfactants, lubricants, stabilizers, thickeners, etc. An appropriate device for inhalation or insufflation may be used for administration. For example, using a known device (for example, a metered dose inhalation device and the like) or a nebulizer, the compound (s) can be administered alone or as a powder of a formulated mixture or as a solution or suspension in combination with a pharmaceutically acceptable vehicle. Dry powder inhalers or the like may be for single or multiple administration use, and dry powders or powder-containing capsules may be used in such devices. Alternatively, they may be in the form of aerosol pressurized sprays or the like using an appropriate propellant, for example, a preferred gas such as chlorofluoroalkane, hydrofluoroalkane, carbon dioxide, or the like.

En general, para administracion por via oral, la dosificacion diaria es deseablemente aproximadamente 0,001 a 100 mg/kg, preferentemente 0,005 a 30 mg/kg, y mas preferentemente 0,01 a 10 mg/kg de peso corporal, administrada como una dosis unica o en 2 a 4 dosis divididas. Para administracion intravenosa, la dosificacion diaria es deseablemente aproximadamente 0,0001 a 10 mg/kg de peso corporal, administrada en una o varias dosis por dfa. Asimismo, para formulaciones transmucosa, la dosificacion diaria es aproximadamente 0,001 a 100 mg/kg de peso corporal, administrada en una o varios dosis por dfa. La dosificacion puede determinarse segun convenga para cada caso en vista del smtoma, edad, sexo, etc.In general, for oral administration, the daily dosage is desirably about 0.001 to 100 mg / kg, preferably 0.005 to 30 mg / kg, and more preferably 0.01 to 10 mg / kg of body weight, administered as a single dose. or in 2 to 4 divided doses. For intravenous administration, the daily dosage is desirably about 0.0001 to 10 mg / kg body weight, administered in one or several doses per day. Also, for transmucosal formulations, the daily dosage is approximately 0.001 to 100 mg / kg of body weight, administered in one or several doses per day. The dosage can be determined as appropriate for each case in view of the symptom, age, sex, etc.

Los compuestos de formula (I) pueden usarse en combinacion con diversos agentes terapeuticos o profilacticos para enfermedades contra las que los compuestos de formula (I) senan eficaces. En general, cuando un agente antitumoral se administra solo durante quimioterapia para el tumor, particularmente tumor maligno, el agente antitumoral tiene un lfmite en su efecto en terminos de efectos secundarios y similares, y asf frecuentemente deja de producir un efecto antitumoral suficiente. Por este motivo, en casos clmicos, se usa terapia multifarmacos en la que se combinan dos o mas farmacos con diferentes mecanismos de accion. Combinando agentes antitumorales con diferentes mecanismos de accion, esta terapia de combinacion tiene como objetivo reducir los efectos secundarios y/o potenciar el efecto antitumoral deseado, por ejemplo, 1) para reducir el numero de poblacion de celulas no sensibles, 2) para prevenir o retardar el desarrollo de la resistencia al farmaco, 3) para dispersar la toxicidad por la combinacion de farmacos con diferentes niveles de toxicidad, y similares. En tal terapia de combinacion, los farmacos pueden administrarse simultaneamente o por separado en sucesion o a intervalos de tiempo deseados. Las formulaciones para administracion simultanea pueden estar en tanto en forma mixta como separada.The compounds of formula (I) can be used in combination with various therapeutic or prophylactic agents for diseases against which the compounds of formula (I) are effective. In general, when an antitumor agent is administered only during chemotherapy for the tumor, particularly malignant tumor, the antitumor agent has a limit in its effect in terms of side effects and the like, and thus frequently ceases to produce a sufficient antitumor effect. For this reason, in climactic cases, multi-drug therapy is used in which two or more drugs are combined with different mechanisms of action. By combining antitumor agents with different mechanisms of action, this combination therapy aims to reduce the side effects and / or enhance the desired antitumor effect, for example, 1) to reduce the number of non-sensitive cell populations, 2) to prevent or retard the development of drug resistance, 3) to disperse toxicity by combining drugs with different levels of toxicity, and the like. In such combination therapy, the drugs can be administered simultaneously or separately in succession or at desired time intervals. Formulations for simultaneous administration can be in both mixed and separate form.

Los farmacos que pueden combinarse incluyen quimioterapeuticos (por ejemplo, agente alquilante, antimetabolito y similares), agentes inmunoterapeuticos, agentes terapeuticos hormonales e inhibidores de factores de crecimiento celulares, mas espedficamente farmacos tales como cisplatino, carboplatino, paclitaxel, docetaxel, gemcitabina, irinotecan, vinorelbina, bevacizumab, pemetrexed y similares.The drugs that can be combined include chemotherapeutics (eg, alkylating agent, antimetabolite and the like), immunotherapeutic agents, hormonal therapeutic agents and cell growth factor inhibitors, more specifically drugs such as cisplatin, carboplatin, paclitaxel, docetaxel, gemcitabine, irinotecan, vinorelbine, bevacizumab, pemetrexed and the like.

EJEMPLOSEXAMPLES

Como preparar los compuestos de formula (1) se explicara adicionalmente en mas detalle a modo de los siguientes ejemplos. Debe observarse que la presente invencion no se limita a los compuestos mostrados en los siguientes ejemplos. Ademas, como preparar los compuestos de partida se muestra en los ejemplos de preparacion. Los procesos para preparar los compuestos de formula (I) no estan limitados solo a aquellos en realidad mostrados en los siguientes ejemplos, y los compuestos de formula (I) tambien pueden prepararse por cualquier combinacion de estos procesos o por cualquier proceso obvio para aquellos expertos en la materia.How to prepare the compounds of formula (1) will be further explained in more detail by way of the following examples. It should be noted that the present invention is not limited to the compounds shown in the following examples. In addition, how to prepare the starting compounds is shown in the preparation examples. The processes for preparing the compounds of formula (I) are not limited only to those actually shown in the following examples, and the compounds of formula (I) can also be prepared by any combination of these processes or by any obvious process for those experts. in the matter.

En los ejemplos, ejemplos de preparacion y tablas mostrados a continuacion, se usan las siguientes abreviaturas segun se necesite.In the examples, preparation examples and tables shown below, the following abbreviations are used as needed.

Rex: Ejemplo de preparacion N°., Ej: Ejemplo N°., Estructura: formula estructural qrnmica, Datos: datos ffsicos y qmmicos (FAB+: FAB-EM [M+H]+, ESI+: ESI-EM [M+H]+, APCI/ESI+: APCI/ESI-EM [M+H]+ (APCI/ESI significa medicion simultanea de APCI y ESI), FAB-: FAB-EM [M-H]-, ESI-: ESI-EM [M-H]-, APCI-: APCI-EM [M-H]-, RMN 1H (CDCh): 6 (ppm) de picos de RMN 1H en cloroformo-d, RMN 1H (CD3OD): 6 (ppm) de picos de RMN 1H en metanol- d, RMN 1H (CDCl3+CD3OD): 6 (ppm) de picos de RMN 1H en una disolucion mixta de cloroformo-d y metanol-d, RMN 1H (DMSO-d6): 6 (ppm) de picos de RMN 1H en DMSO-d6, XRD: angulo de difraccion 20(°) del pico principal en la medicion de difraccion de rayos X de polvo, HCl: que significa que el producto previsto se obtuvo como clorhidrato, 2HCl: que significa que el producto previsto se obtuvo como diclorhidrato, TsOH: que significa que el producto previsto se obtuvo como una sal de acido p-toluenosulfonico, HFM: que significa que el producto previstoRex: Preparation example No., Ex: Example No., Structure: chemical structural formula, Data: physical and chemical data (FAB +: FAB-EM [M + H] +, ESI +: ESI-EM [M + H ] +, APCI / ESI +: APCI / ESI-EM [M + H] + (APCI / ESI means simultaneous measurement of APCI and ESI), FAB-: FAB-EM [MH] -, ESI-: ESI-EM [MH ] -, APCI-: APCI-MS [MH] -, 1H NMR (CDCh): 6 (ppm) of 1H NMR peaks in chloroform-d, 1H NMR (CD3OD): 6 (ppm) of 1H NMR peaks in methanol-d, 1H NMR (CDCl3 + CD3OD): 6 (ppm) of 1H NMR peaks in a mixed solution of chloroform-d and methanol-d, 1H NMR (DMSO-d6): 6 (ppm) of NMR peaks 1H in DMSO-d6, XRD: diffraction angle 20 (°) of the main peak in the measurement of powder X-ray diffraction, HCl: which means that the intended product was obtained as hydrochloride, 2HCl: which means that the expected product was obtained as dihydrochloride, TsOH: which means that the intended product was obtained as a salt of p-toluenesulfonic acid, HFM: which means that the intended product

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se obtuvo como una sal del acido hemifumarico, FM: que significa que el producto previsto se obtuvo como una sal del acido fumarico, Me: metilo, Et: etilo, nPr: propilo normal, iPr: isopropilo, cPr: ciclopropilo, cHex: ciclohexilo, Ph: fenilo, Bn: bencilo, Boc: terc-butiloxicarbonilo, Ac: acetilo. Sin: proceso de preparacion (que indica que el producto previsto se preparo a partir de materiales de partida correspondientes como en el Ejemplo de preparacion indicado o Ejemplo). En las tablas mostradas en los Ejemplos de preparacion o Ejemplos, hay isomeros cis-trans y sus configuraciones estan sin resolver, pero en cuanto a los compuestos que muestran una configuracion unica de una de cis y trans, no se hace indicacion de la configuracion en sus formulas estructurales qmmicas y, en su lugar, el sfmbolo “*” se da a sus N° de ejemplo de preparacion o N° de ejemplo. Los compuestos a los que se le da el mismo numero tras el sfmbolo “*” indican que uno de los compuestos es una forma cis y la otra es una forma trans.it was obtained as a salt of hemifumaric acid, FM: which means that the intended product was obtained as a salt of smoking acid, Me: methyl, Et: ethyl, nPr: normal propyl, iPr: isopropyl, cPr: cyclopropyl, cHex: cyclohexyl , Ph: phenyl, Bn: benzyl, Boc: tert-butyloxycarbonyl, Ac: acetyl. Without: preparation process (indicating that the intended product was prepared from corresponding starting materials as in the indicated Preparation Example or Example). In the tables shown in the Preparation Examples or Examples, there are cis-trans isomers and their configurations are unresolved, but as for the compounds that show a unique configuration of one of cis and trans, there is no indication of the configuration in its chemical structural formulas and, instead, the symbol "*" is given to its preparation example number or example number. Compounds that are given the same number after the symbol "*" indicate that one of the compounds is a cis form and the other is a trans form.

La medicion de la difraccion de rayos X de polvo se realizo usando RINT-TTR II bajo las siguientes condiciones; tubo: Cu, corriente del tubo: 300 mA, voltaje del tubo: 50 kV, anchura de muestreo: 0,020°, tasa de barrido: 4°/min, longitud de onda: 1,54056 A, intervalo del angulo de difraccion medido (20): 2,5 a 40°. Debe observarse que la difraccion de rayos X de polvo no debe entenderse estrictamente, debido a que, debido a la naturaleza de los datos de difraccion de rayos X de polvo, el espacio de red cristalina y el patron global son importantes en la determinacion de la identidad del cristal, y la intensidad relativa puede variar en algun grado dependiendo de la direccion de crecimiento del cristal, tamano de partfcula y condiciones de medicion.The measurement of powder X-ray diffraction was performed using RINT-TTR II under the following conditions; tube: Cu, tube current: 300 mA, tube voltage: 50 kV, sampling width: 0.020 °, scan rate: 4 ° / min, wavelength: 1.54056 A, measured diffraction angle range ( 20): 2.5 to 40 °. It should be noted that powder X-ray diffraction should not be strictly understood, because, due to the nature of the dust X-ray diffraction data, the crystalline net space and the global pattern are important in determining the Crystal identity, and the relative intensity may vary to some extent depending on the direction of crystal growth, particle size and measurement conditions.

Ejemplo de preparacion 4Preparation Example 4

Se calento una mezcla de acido 4-metil-3-nitrobenzoico (1,97 g) y cloruro de tionilo (6 ml) a reflujo durante 18 horas. El lfquido de reaccion se concentro a presion reducida, seguido de un proceso azeotropico con tolueno para dar una aceite rojo-marron. A una mezcla del aceite rojo-marron y THF (25 ml) se anadio dietilamina (2,6 ml) bajo enfriamiento con hielo y se agito a temperatura ambiente durante 5 horas. El lfquido de reaccion se vertio en agua y se extrajo con acetato de etilo. La fase organica se lavo con cloruro sodico acuoso saturado y a continuacion se seco sobre sulfato de sodio anhidro, y el disolvente se separo por destilacion a presion reducida dando N,N-dietil-4- metil-3-nitrobenzamida (2,61 g) como un aceite marron.A mixture of 4-methyl-3-nitrobenzoic acid (1.97 g) and thionyl chloride (6 ml) was heated at reflux for 18 hours. The reaction liquid was concentrated under reduced pressure, followed by an azeotropic process with toluene to give a red-brown oil. To a mixture of the red-brown oil and THF (25 ml) was added diethylamine (2.6 ml) under ice cooling and stirred at room temperature for 5 hours. The reaction liquid was poured into water and extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give N, N-diethyl-4- methyl-3-nitrobenzamide (2.61 g) Like a brown oil

Ejemplo de preparacion 41Preparation Example 41

A una mezcla de cloruro de 2-metoxi-4-nitrobencenosulfonilo (600 mg) y THF (5 ml) se anadio una mezcla de piperidina (406 mg) y THF (1 ml) y se agito a temperatura ambiente durante 12 horas. Despues de la adicion de 10 % de acido clorhndrico, el lfquido de reaccion se extrajo con acetato de etilo. La fase organica se lavo con cloruro sodico acuoso saturado y a continuacion se seco sobre sulfato de sodio anhidro, y el disolvente se separo por destilacion a presion reducida dando 1-[(2-metoxi-4-nitrofenil)sulfonil]piperidina (714 mg) como un solido amarillo.To a mixture of 2-methoxy-4-nitrobenzenesulfonyl chloride (600 mg) and THF (5 ml) a mixture of piperidine (406 mg) and THF (1 ml) was added and stirred at room temperature for 12 hours. After the addition of 10% hydrochloric acid, the reaction liquid was extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure giving 1 - [(2-methoxy-4-nitrophenyl) sulfonyl] piperidine (714 mg) Like a yellow solid

Ejemplo de preparacion 48Preparation Example 48

Una mezcla de acido 2-fluoro-5-nitrobenzoico (600 mg) y cloruro de tionilo (2 ml) se calento a reflujo durante 15 horas. El lfquido de reaccion se concentro a presion reducida, seguido de un proceso azeotropico con tolueno dando un cristal amarillo. A una mezcla del cristal amarillo y THF (11 ml) se anadieron trietilamina (0,47 ml) e isopropilamina (0,29 ml) bajo enfriamiento con hielo y se agito a temperatura ambiente durante 5 horas. El lfquido de reaccion se vertio en agua y se extrajo con acetato de etilo. La fase organica se lavo con cloruro sodico acuoso saturado y a continuacion se seco sobre sulfato de sodio anhidro, y el disolvente se separo por destilacion a presion reducida dando un cristal amarillo. A una mezcla del cristal amarillo (723 mg) y metanol (8 ml) y agua (3 ml) se anadieron cloruro de amonio (2,05 g) y polvo de cinc (2,09 g), y la mezcla se calento a reflujo durante 3 horas. Despues de la filtracion de la suspension de reaccion a traves de Celite, el filtrado se concentro a presion reducida. El residuo se vertio en hidrogenocarbonato de sodio acuoso saturado y se extrajo con acetato de etilo. La fase organica se lavo con cloruro sodico acuoso saturado y a continuacion se seco sobre sulfato de sodio anhidro, y el disolvente se separo por destilacion a presion reducida. El residuo se purifico por cromatograffa en columna de gel de sflice (eluyente; cloroformo:metanol) dando 5-amino-2-fluoro-N-isopropilbenzamida (527 mg) como un cristal marron claro.A mixture of 2-fluoro-5-nitrobenzoic acid (600 mg) and thionyl chloride (2 ml) was heated at reflux for 15 hours. The reaction liquid was concentrated under reduced pressure, followed by an azeotropic process with toluene giving a yellow crystal. To a mixture of the yellow crystal and THF (11 ml) were added triethylamine (0.47 ml) and isopropylamine (0.29 ml) under ice cooling and stirred at room temperature for 5 hours. The reaction liquid was poured into water and extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give a yellow crystal. To a mixture of the yellow crystal (723 mg) and methanol (8 ml) and water (3 ml) were added ammonium chloride (2.05 g) and zinc powder (2.09 g), and the mixture was heated to reflux for 3 hours. After filtration of the reaction suspension through Celite, the filtrate was concentrated under reduced pressure. The residue was poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent; chloroform: methanol) to give 5-amino-2-fluoro-N-isopropylbenzamide (527 mg) as a light brown crystal.

Ejemplo de preparacion 160Preparation Example 160

A una mezcla de 3,5-dicloro-6-etilpirazin-2-carboxamida (1,0 g) y DMF (15 ml) se anadio cloruro de tionilo (1 ml) a temperatura ambiente y se agito durante 20 minutos. El lfquido de reaccion se vertio en agua fria con hielo y se extrajo con acetato de etilo. La fase organica se lavo con cloruro sodico acuoso saturado y a continuacion se seco sobre sulfato de sodio anhidro, y el disolvente se separo por destilacion a presion reducida. El residuo se purifico por cromatograffa en columna de gel de sflice (eluyente; acetato de etilo:n-hexano) dando 3,5-dicloro-6-etilpirazin-2- carbonitrilo (608 mg) como un aceite ligeramente amarillo.To a mixture of 3,5-dichloro-6-ethylpyrazin-2-carboxamide (1.0 g) and DMF (15 ml), thionyl chloride (1 ml) was added at room temperature and stirred for 20 minutes. The reaction liquid was poured into cold water with ice and extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent; ethyl acetate: n-hexane) to give 3,5-dichloro-6-ethylpyrazin-2-carbonitrile (608 mg) as a slightly yellow oil.

Ejemplo de preparacion 194Preparation Example 194

A una disolucion de una mezcla de 5-cloro-3-{[4-(4-metilpiperazin-1-il)fenil]amino}pirazin-2-carboxilato de metilo (Ejemplo de preparacion 193) (20 mg) y THF (2 ml) se anadio clorhidrato de O-metilhidroxilamina (14 mg). Al lfquidoAt a solution of a mixture of methyl 5-chloro-3 - {[4- (4-methylpiperazin-1-yl) phenyl] amino} pyrazine-2-carboxylate (Preparation Example 193) (20 mg) and THF ( 2 ml) O-methylhydroxylamine hydrochloride (14 mg) was added. To the liquid

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de reaccion se anadio hexametildisilazida de litio (0,39 ml, disolucion 1 M de THF) bajo enfriamiento con hielo y se agito durante 20 minutos. El Kquido de reaccion se vertio en hidrogenocarbonato de sodio acuoso saturado y se extrajo con acetato de etilo, y a continuacion la fase organica se lavo con cloruro sodico acuoso saturado. Despues de secar sobre sulfato de sodio anhidro, el disolvente se separo por destilacion a presion reducida dando 5-cloro-N- metoxi-3-{[4-(4-metilpiperazin-1-il)fenil]amino}pirazin-2-carboxamida (21 mg) como un polvo amarillo.The reaction was added lithium hexamethyldisilazide (0.39 ml, 1 M solution of THF) under ice cooling and stirred for 20 minutes. The reaction liquid was poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate, and then the organic phase was washed with saturated aqueous sodium chloride. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to give 5-chloro-N-methoxy-3 - {[4- (4-methylpiperazin-1-yl) phenyl] amino} pyrazine-2- Carboxamide (21 mg) as a yellow powder.

Ejemplo de preparacion 240Preparation Example 240

A una mezcla de 1-(2-yodo-4-nitrofenil)-4-metilpiperazina (Ejemplo de preparacion 241) (406 mg) se anadieron tolueno (3 ml) y agua (3 ml), carbonato sodico (496 mg), acido fenilboronico (157 mg) y tetraquis(trifenilfosfina)paladio (68 mg) en una atmosfera de argon y se agito durante la noche a 110 °C. El lfquido de reaccion se vertio en agua y se extrajo con acetato de etilo. La fase organica se lavo con cloruro sodico acuoso saturado y a continuacion se seco sobre sulfato de sodio anhidro, y el disolvente se separo por destilacion a presion reducida. El residuo se purifico por cromatograffa en columna de gel de sflice (eluyente; cloroformo/metanol) dando 1-metil-4-(5-nitrobifenil-2-il)piperazina (348 mg) como un aceite amarillo-marron.To a mixture of 1- (2-iodo-4-nitrophenyl) -4-methylpiperazine (Preparation Example 241) (406 mg) were added toluene (3 ml) and water (3 ml), sodium carbonate (496 mg), Phenylboronic acid (157 mg) and tetrakis (triphenylphosphine) palladium (68 mg) in an argon atmosphere and stirred overnight at 110 ° C. The reaction liquid was poured into water and extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent; chloroform / methanol) to give 1-methyl-4- (5-nitrobiphenyl-2-yl) piperazine (348 mg) as a yellow-brown oil.

Ejemplo de preparacion 244Preparation Example 244

A una mezcla de N-[2-(4-metilpiperazin-1-il)-5-nitrofenil]acetamida (433 mg) y DMF (5 ml) se anadio 63 % de hidruro de sodio en aceite (66 mg) bajo enfriamiento con hielo y se agito a temperatura ambiente durante 1 hora. El lfquido de reaccion se enfrio en hielo de nuevo, y se anadio yoduro de metilo (0,11 ml) y se agito a temperatura ambiente durante 4 horas. El lfquido de reaccion se vertio en cloruro de amonio acuoso saturado y se extrajo con acetato de etilo. La fase organica se lavo con cloruro sodico acuoso saturado y a continuacion se seco sobre sulfato de sodio anhidro, y el disolvente se separo por destilacion a presion reducida. El residuo se purifico por cromatograffa en columna de gel de sflice (eluyente; cloroformo:metanol) dando N-metil-N-[2-(4-metilpiperazin-1-il)-5- nitrofenil]acetamida (200 mg) como un solido naranja.To a mixture of N- [2- (4-methylpiperazin-1-yl) -5-nitrophenyl] acetamide (433 mg) and DMF (5 ml) 63% of sodium hydride in oil (66 mg) was added under cooling with ice and stirred at room temperature for 1 hour. The reaction liquid was cooled on ice again, and methyl iodide (0.11 ml) was added and stirred at room temperature for 4 hours. The reaction liquid was poured into saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent; chloroform: methanol) to give N-methyl-N- [2- (4-methylpiperazin-1-yl) -5-nitrophenyl] acetamide (200 mg) as a solid orange

Ejemplo de preparacion 246Preparation Example 246

A una mezcla de (4-oxociclohexil)carbamato de terc-butilo (3,04 g) y THF (100 ml) se anadio etil-litio (disolucion 0,5 M de benceno-ciclohexano) (56,8 ml) a -78 °C y se agito durante 4 horas hasta que llego a -50 °C. Despues de la adicion de agua (150 ml), el lfquido de reaccion se calento a temperatura ambiente y se extrajo con acetato de etilo. La fase organica se lavo con cloruro sodico acuoso saturado y a continuacion se seco sobre sulfato de sodio, y el disolvente se separo por destilacion. El residuo resultante se purifico por cromatograffa en columna de gel de sflice (eluyente; cloroformo:metanol = 30:1) y se purifico adicionalmente (eluyente; n-hexano:acetato de etilo = 2:1 a 1:1) dando (4-etil-4-hidroxiciclohexil)carbamato de terc-butilo (Ejemplo de preparacion 246) (0,202 g), que fue un producto de baja polaridad, como un solido blanco y (4-etil-4-hidroxiciclohexil)carbamato de terc-butilo (Ejemplo de preparacion 248), que fue un producto de alta polaridad, como un jarabe incoloro.To a mixture of tert-butyl (4-oxocyclohexyl) carbamate (3.04 g) and THF (100 ml) was added ethyl lithium (0.5 M solution of benzene-cyclohexane) (56.8 ml) to - 78 ° C and stirred for 4 hours until it reaches -50 ° C. After the addition of water (150 ml), the reaction liquid was heated to room temperature and extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride and then dried over sodium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (eluent; chloroform: methanol = 30: 1) and further purified (eluent; n-hexane: ethyl acetate = 2: 1 to 1: 1) to give (4 tert-butyl-4-hydroxycyclohexyl) carbamate (Preparation Example 246) (0.202 g), which was a low polar product, such as a white solid and tert-butyl (4-ethyl-4-hydroxycyclohexyl) carbamate (Preparation example 248), which was a high polarity product, such as a colorless syrup.

Ejemplo de preparacion 247Preparation Example 247

A una mezcla de (4-etil-4-hidroxiciclohexil)carbamato de terc-butilo (Ejemplo de preparacion 246) (0,202 g) y dioxano (2 ml) se anadio 26 % de cloruro de hidrogeno-dioxano (1,1 ml) bajo enfriamiento con hielo y se agito a temperatura ambiente durante 12 horas. El disolvente se separo por destilacion dando clorhidrato de 4-amino-1-etilciclohexanol (0,140 g) como un solido viscoso blanco.To a mixture of tert-butyl (4-ethyl-4-hydroxycyclohexyl) carbamate (Preparation Example 246) (0.202 g) and dioxane (2 ml) was added 26% hydrogen-dioxane chloride (1.1 ml) under ice cooling and stirred at room temperature for 12 hours. The solvent was distilled off to give 4-amino-1-ethylcyclohexanol hydrochloride (0.134 g) as a white viscous solid.

Ejemplo de preparacion 249Preparation Example 249

A una mezcla de (4-etil-4-hidroxiciclohexil)carbamato de terc-butilo (Ejemplo de preparacion 248) (0,256 g) y dioxano (2 ml) se anadio 26 % de cloruro de hidrogeno-dioxano (1,4 ml) bajo enfriamiento con hielo y se agito a temperatura ambiente durante 17 horas. El solido precipitado se recogio por filtracion dando clorhidrato de 4-amino-1- etilciclohexanol (0,152 g) como un solido blanco.To a mixture of tert-butyl (4-ethyl-4-hydroxycyclohexyl) carbamate (Preparation Example 248) (0.256 g) and dioxane (2 ml) was added 26% hydrogen-dioxane chloride (1.4 ml) under ice cooling and stirred at room temperature for 17 hours. The precipitated solid was collected by filtration giving 4-amino-1- ethylcyclohexanol hydrochloride (0.152 g) as a white solid.

Ejemplo de preparacion 250Preparation Example 250

A una mezcla de (4-oxociclohexil)carbamato de terc-butilo (3,04 g) y THF (100 ml) se anadio isopropil-litio (disolucion 0,7 M de pentano) (40,3 ml) a -78 °C y se agito durante 4 horas hasta que llego a -50 °C. Despues de la adicion, de agua (150 ml), el lfquido de reaccion se calento a temperatura ambiente y se extrajo con acetato de etilo. La fase organica se lavo con cloruro sodico acuoso saturado y a continuacion se seco sobre sulfato de sodio, y el disolvente se separo por destilacion. El residuo resultante se purifico por cromatograffa en columna de gel de sflice (eluyente; n-hexano:acetato de etilo = 3:1) y se purifico adicionalmente (eluyente; cloroformo:metanol = 30:1) dando (4- isopropil-4-hidroxiciclohexil)carbamato de terc-butilo (Ejemplo de preparacion 250) (0,854 g), que fue un producto de baja polaridad, como un solido blanco y (4-isopropil-4-hidroxiciclohexil)carbamato de terc-butilo (Ejemplo de preparacion 252) (0,179 g), que fue un producto de alta polaridad, como un aceite amarillo.To a mixture of tert-butyl (4-oxocyclohexyl) carbamate (3.04 g) and THF (100 ml), isopropyl lithium (0.7 M solution of pentane) (40.3 ml) was added at -78 ° C and stirred for 4 hours until it reached -50 ° C. After the addition of water (150 ml), the reaction liquid was heated to room temperature and extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride and then dried over sodium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 3: 1) and further purified (eluent; chloroform: methanol = 30: 1) giving (4- isopropyl-4 tert-butyl hydroxycyclohexyl) carbamate (Preparation Example 250) (0.854 g), which was a low polar product, such as a white solid and tert-butyl (4-isopropyl-4-hydroxycyclohexyl) carbamate (Preparation example 252) (0.179 g), which was a high polarity product, such as a yellow oil.

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Ejemplo de preparacion 251Preparation Example 251

A una mezcla de (4-isopropil-4-hidroxiciclohexil)carbamato de terc-butilo (Ejemplo de preparacion 250) (0,392 g) y dioxano (3 ml) se anadio 26 % de cloruro de hidrogeno-dioxano (2,0 ml) bajo enfriamiento con hielo y se agito a temperatura ambiente durante 18 horas. El solido precipitado se recogio por filtracion dando clorhidrato de 4-amino- 1-isopropilciclohexanol (0,190 g) como un solido blanco.To a mixture of tert-butyl (4-isopropyl-4-hydroxycyclohexyl) carbamate (Preparation Example 250) (0.392 g) and dioxane (3 ml) was added 26% hydrogen-dioxane chloride (2.0 ml) under ice cooling and stirred at room temperature for 18 hours. The precipitated solid was collected by filtration to give 4-amino-1-isopropylcyclohexanol hydrochloride (0.190 g) as a white solid.

Ejemplo de preparacion 253Preparation Example 253

A una mezcla de (4-isopropil-4-hidroxiciclohexil)carbamato de terc-butilo (Ejemplo de preparacion 252) (0,179 g) y dioxano (1,5 ml) se anadio 26% cloruro de hidrogeno-dioxano (0,9 ml) bajo enfriamiento con hielo y se agito a temperatura ambiente durante 18 horas. El solido precipitado se recogio por filtracion dando clorhidrato de 4-amino- 1-isopropilciclohexanol (0,086 g) como un solido blanco.To a mixture of tert-butyl (4-isopropyl-4-hydroxycyclohexyl) carbamate (Preparation Example 252) (0.179 g) and dioxane (1.5 ml) was added 26% hydrogen-dioxane chloride (0.9 ml ) under ice cooling and stirred at room temperature for 18 hours. The precipitated solid was collected by filtration to give 4-amino-1-isopropylcyclohexanol hydrochloride (0.086 g) as a white solid.

Ejemplo de preparacion 287Preparation Example 287

A una mezcla de propano-2-tiol (3,30 ml), carbonato de potasio (6,60 g) y DMF (40 ml) se anadio 1-fluoro-4-metil-2- nitrobenceno (4,85 g) y se agito a temperatura ambiente durante 5 horas. Despues de la adicion de agua, el lfquido de reaccion se extrajo con acetato de etilo, y el extracto se lavo con agua y cloruro sodico acuoso saturado. Despues de secar sobre sulfato de sodio anhidro, el disolvente se separo por destilacion a presion reducida dando 1-(isopropilsulfanil)-4-metil-2-nitrobenceno (6,60 g) como un aceite amarillo.To a mixture of propane-2-thiol (3.30 ml), potassium carbonate (6.60 g) and DMF (40 ml) 1-fluoro-4-methyl-2-nitrobenzene (4.85 g) was added and stirred at room temperature for 5 hours. After the addition of water, the reaction liquid was extracted with ethyl acetate, and the extract was washed with water and saturated aqueous sodium chloride. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to give 1- (isopropylsulfanyl) -4-methyl-2-nitrobenzene (6.60 g) as a yellow oil.

Ejemplo de preparacion 291Preparation Example 291

A una mezcla de 1-(isopropilsulfanil)-4-metil-2-nitrobenceno (Ejemplo de preparacion 287) (6,60 g) y cloroformo (150 ml) se anadio acido m-cloroperbenzoico (18,0 g) y se agito a 50 °C durante 12 horas. Despues de enfriarse el lfquido de reaccion, se anadieron hidrogenocarbonato de sodio acuoso saturado y 5 % de sulfito de sodio acuoso, y el lfquido de reaccion se extrajo con cloroformo. Despues de secarse la fase organica sobre sulfato de sodio anhidro, el disolvente se separo por destilacion a presion reducida dando 2-(isopropilsulfonil)-4-metil-1-nitrobenceno (7,41 g) como un solido amarillo.To a mixture of 1- (isopropylsulfanyl) -4-methyl-2-nitrobenzene (Preparation example 287) (6.60 g) and chloroform (150 ml), m-chloroperbenzoic acid (18.0 g) was added and stirred at 50 ° C for 12 hours. After cooling the reaction liquid, saturated aqueous sodium hydrogen carbonate and 5% aqueous sodium sulphite were added, and the reaction liquid was extracted with chloroform. After drying the organic phase over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to give 2- (isopropylsulfonyl) -4-methyl-1-nitrobenzene (7.41 g) as a yellow solid.

Ejemplo de preparacion 292Preparation Example 292

A una mezcla de 2-(isopropilsulfonil)-4-metil-1-nitrobenceno (Ejemplo de preparacion 291) (7,41 g) y acido acetico (70 ml) se anadio polvo de hierro (5,43 g) y se agito a 80 °C durante 3 horas. A partir de aqrn, se eliminaron los materiales insolubles en el lfquido de reaccion, y el disolvente se separo por destilacion a presion reducida. Despues de la adicion de acetato de etilo (150 ml) y la eliminacion de materiales insolubles, el residuo se lavo con agua y cloruro sodico acuoso saturado. Despues de secar sobre sulfato de sodio anhidro, el disolvente se separo por destilacion a presion reducida. El residuo se lavo con acetato de etilo-eter diisopropflico dando 2-(isopropilsulfonil)-4- metilanilina (3,86 g) como un solido amarillo claro.To a mixture of 2- (isopropylsulfonyl) -4-methyl-1-nitrobenzene (Preparation Example 291) (7.41 g) and acetic acid (70 ml) iron powder (5.43 g) was added and stirred at 80 ° C for 3 hours. From here, insoluble materials in the reaction liquid were removed, and the solvent was distilled off under reduced pressure. After the addition of ethyl acetate (150 ml) and the removal of insoluble materials, the residue was washed with water and saturated aqueous sodium chloride. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was washed with ethyl acetate-diisopropyl ether giving 2- (isopropylsulfonyl) -4-methylaniline (3.86 g) as a light yellow solid.

Ejemplo de preparacion 298Preparation Example 298

A una mezcla de 55 % de hidruro de sodio en aceite (733 mg) y DMF (20 ml) se anadieron una mezcla de 3- (metilsulfonil)anilina (1,44 g) y THF (20 ml) bajo enfriamiento con hielo y se agito durante 30 minutos bajo enfriamiento con hielo. Despues de la adicion gota a gota de una mezcla de 4,6-dicloro-2-(metilsulfanil)pirimidin-5- carboxamida (2,0 g) y DMF (30 ml) durante 15 minutos, el lfquido de reaccion se agito adicionalmente bajo enfriamiento con hielo durante 15 minutos. Despues de la adicion de 10% de acido cftrico acuoso (300 ml) y extraccion con acetato de etilo, la fase organica se lavo con cloruro sodico acuoso saturado. Despues de secar sobre sulfato de magnesio anhidro, el disolvente se concentro, y el solido precipitado se recogio por filtracion y se seco dando 4-cloro-2-(metilsulfanil)-6-{[3-(metilsulfonil)fenil]amino}pirimidin-5-carboxamida (1,95 g) como un solido amarillo claro.To a mixture of 55% sodium hydride in oil (733 mg) and DMF (20 ml) a mixture of 3- (methylsulfonyl) aniline (1.44 g) and THF (20 ml) was added under ice cooling and stirred for 30 minutes under ice cooling. After the dropwise addition of a mixture of 4,6-dichloro-2- (methylsulfanyl) pyrimidine-5-carboxamide (2.0 g) and DMF (30 ml) for 15 minutes, the reaction liquid was further stirred under ice cooling for 15 minutes. After the addition of 10% aqueous citric acid (300 ml) and extraction with ethyl acetate, the organic phase was washed with saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent was concentrated, and the precipitated solid was collected by filtration and dried to give 4-chloro-2- (methylsulfanyl) -6 - {[3- (methylsulfonyl) phenyl] amino} pyrimidin -5-carboxamide (1.95 g) as a light yellow solid.

Ejemplo de preparacion 299Preparation Example 299

A una mezcla de 4-cloro-2-(metilsulfanil)-6-{[3-(metilsulfonil)fenil]amino}pirimidin-5-carboxamida (Ejemplo de preparacion 298) (1,95 g) y DMSO (30 ml) se anadieron carbonato de potasio (1,81 g) y disolucion al 30% de peroxido de hidrogeno (2,65 ml) y se agito a 50 °C durante 1,5 horas. El lfquido de reaccion se enfrio en hielo, y se anadieron acido clorhfdrico 1 M (25 ml) y a partir de aqrn agua (150 ml) y se agito durante 30 minutos. El solido precipitado se recogio por filtracion y se lavo con agua dando 2-(metilsulfanil)-4-{[3-(metilsulfonil)fenil]amino}-6-oxo- 1,6-dihidropirimidin-5-carboxamida (1,40 g) como un solido amarillo claro.To a mixture of 4-chloro-2- (methylsulfanyl) -6 - {[3- (methylsulfonyl) phenyl] amino} pyrimidin-5-carboxamide (Preparation example 298) (1.95 g) and DMSO (30 ml) Potassium carbonate (1.81 g) and 30% solution of hydrogen peroxide (2.65 ml) were added and stirred at 50 ° C for 1.5 hours. The reaction liquid was cooled on ice, and 1M hydrochloric acid (25 ml) was added and from this water (150 ml) and stirred for 30 minutes. The precipitated solid was collected by filtration and washed with water giving 2- (methylsulfanyl) -4 - {[3- (methylsulfonyl) phenyl] amino} -6-oxo- 1,6-dihydropyrimidine-5-carboxamide (1.40 g) as a light yellow solid.

Ejemplo de preparacion 304Preparation Example 304

A una mezcla de 4-cloro-6-[(6-metilpiridin-3-il)amino]-2-(metilsulfanil)pirimidin-5-carboxamida (Ejemplo de preparacion 303) (51 mg) y metanol (1 ml) se anadio metoxido de sodio (11 mg) bajo enfriamiento con hielo y seTo a mixture of 4-chloro-6 - [(6-methylpyridin-3-yl) amino] -2- (methylsulfanyl) pyrimidin-5-carboxamide (Preparation Example 303) (51 mg) and methanol (1 ml) added sodium methoxide (11 mg) under ice cooling and

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agito durante la noche a temperatura ambiente. Se anadio agua al Ifquido de reaccion, y el solido se recogio por filtracion dando 4-metoxi-6-[(6-metilpiridin-3-il)amino]-2-(metilsulfanil)pirimidin-5-carboxamida (41 mg).I stir overnight at room temperature. Water was added to the reaction liquid, and the solid was collected by filtration to give 4-methoxy-6 - [(6-methylpyridin-3-yl) amino] -2- (methylsulfanyl) pyrimidin-5-carboxamide (41 mg).

Ejemplo de preparacion 311Preparation Example 311

A una mezcla de 4-{[3-(metilcarbamoil)fenil]amino}-2-(metilsulfanil)-6-oxo-1,6-dihidropirimidin-5-carboxamida (Ejemplo de preparacion 306) (500 mg), diclorometano (40 ml) y metanol (40 ml) se anadio una mezcla de Oxone® (922 mg) y agua (10 ml) y se agito a temperatura ambiente durante 18 horas. Al lfquido de reaccion se anadieron cloroformo y agua, y el solido precipitado se recogio por filtracion y se lavo con agua dando 4-{[3- (metilcarbamoil)fenil]amino}-2-(metilsulfinil)-6-oxo-1,6-dihidropirimidin-5-carboxamida (234 mg) como un solido amarillo claro.To a mixture of 4 - {[3- (methylcarbamoyl) phenyl] amino} -2- (methylsulfanyl) -6-oxo-1,6-dihydropyrimidine-5-carboxamide (Preparation Example 306) (500 mg), dichloromethane ( 40 ml) and methanol (40 ml) a mixture of Oxone® (922 mg) and water (10 ml) was added and stirred at room temperature for 18 hours. Chloroform and water were added to the reaction liquid, and the precipitated solid was collected by filtration and washed with water giving 4 - {[3- (methylcarbamoyl) phenyl] amino} -2- (methylsulfinyl) -6-oxo-1, 6-dihydropyrimidin-5-carboxamide (234 mg) as a light yellow solid.

Ejemplo de preparacion 339Preparation Example 339

A una mezcla de 4-metoxi-6-[(6-metoxi-piridin-3-il)amino]-2-(metilsulfanil)pirimidin-5-carboxamida (Ejemplo de preparacion 337) (0,35 g) y agua (2,2 ml) se anadio acido clorhndrico concentrado (2,2 ml) y se agito a 80 °C durante 1,5 horas. Despues de enfriarse el lfquido de reaccion, se anadio hidroxido sodico acuoso 1 M de manera que el lfquido de reaccion fuera casi neutro, y entonces el solido resultante se recogio por filtracion dando 4-[(6-metoxi- piridin-3-il)amino]-2-(metilsulfanil)-6-oxo-1,6-dihidropirimidin-5-carboxamida (0,34 g).To a mixture of 4-methoxy-6 - [(6-methoxy-pyridin-3-yl) amino] -2- (methylsulfanyl) pyrimidin-5-carboxamide (Preparation Example 337) (0.35 g) and water ( 2.2 ml) concentrated hydrochloric acid (2.2 ml) was added and stirred at 80 ° C for 1.5 hours. After cooling the reaction liquid, 1 M aqueous sodium hydroxide was added so that the reaction liquid was almost neutral, and then the resulting solid was collected by filtration giving 4 - [(6-methoxy-pyridin-3-yl) amino] -2- (methylsulfanyl) -6-oxo-1,6-dihydropyrimidin-5-carboxamide (0.34 g).

Ejemplo de preparacion 342Preparation Example 342

A una mezcla de acido 4,6-dicloro-2-(metilsulfanil)pirimidin-5-carboxflico (1,50 g) y diclorometano (15 ml) se anadieron cloruro de oxalilo (1,20 ml) y DMF (0,015 ml) bajo enfriamiento con hielo y se agito 30 minutos bajo enfriamiento con hielo y 2 horas a temperatura ambiente. El disolvente se separo por destilacion a presion reducida, seguido de un proceso azeotropico con tolueno. El residuo resultante se disolvio en THF, seguido de la adicion gota a gota de 40% de metilamina acuosa a -10 °C. Despues de completarse la adicion gota a gota, el lfquido de reaccion se concentro, y se anadio agua. El solido resultante se recogio por filtracion y se lavo con agua dando un solido blanco. El solido se disolvio en acetato de etilo, se lavo con cloruro sodico acuoso saturado, y a continuacion se seco sobre sulfato de magnesio anhidro. El disolvente se separo por destilacion. A una mezcla del residuo resultante y dioxano (20 ml) se anadieron clorhidrato de 3-(metilsulfonil)anilina (432 mg) y N,N-diisopropiletilamina (0,73 ml) y se agito a 100 °C durante 4 horas. Despues de enfriarse, el lfquido de reaccion se diluyo con acetato de etilo y se lavo con cloruro sodico acuoso saturado. Despues de secar sobre sulfato de magnesio anhidro, el disolvente se separo por destilacion y el residuo se purifico por cromatograffa en columna de gel de sflice (eluyente; cloroformo:metanol = 100:0 a 30:1) dando 4-cloro-N-metil-2-(metilsulfanil)-6-{[3-(metilsulfonil)fenil]amino}pirimidin-5- carboxamida (445 mg) como un solido blanco.To a mixture of 4,6-dichloro-2- (methylsulfanyl) pyrimidin-5-carboxylic acid (1.50 g) and dichloromethane (15 ml) were added oxalyl chloride (1.20 ml) and DMF (0.015 ml) under ice cooling and stirred 30 minutes under ice cooling and 2 hours at room temperature. The solvent was distilled off under reduced pressure, followed by an azeotropic process with toluene. The resulting residue was dissolved in THF, followed by the dropwise addition of 40% aqueous methylamine at -10 ° C. After completion of the dropwise addition, the reaction liquid was concentrated, and water was added. The resulting solid was collected by filtration and washed with water giving a white solid. The solid was dissolved in ethyl acetate, washed with saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. The solvent was distilled off. To a mixture of the resulting residue and dioxane (20 ml) 3- (methylsulfonyl) aniline hydrochloride (432 mg) and N, N-diisopropylethylamine (0.73 ml) were added and stirred at 100 ° C for 4 hours. After cooling, the reaction liquid was diluted with ethyl acetate and washed with saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent was distilled off and the residue was purified by silica gel column chromatography (eluent; chloroform: methanol = 100: 0 to 30: 1) giving 4-chloro-N- Methyl-2- (methylsulfanyl) -6 - {[3- (methylsulfonyl) phenyl] amino} pyrimidine-5-carboxamide (445 mg) as a white solid.

Ejemplo de preparacion 346Preparation Example 346

A una mezcla de 4-cloro-2-(metilsulfanil)-6-(quinolin-3-ilamino)pirimidin-5-carboxamida (Ejemplo de preparacion 344) (0,68 g) y acetato sodico (0,80 g) se anadio DMF (7 ml) y se agito a 100 °C durante 6 horas. Despues de que el lfquido de reaccion volviera a temperatura ambiente, se anadio agua, y el solido resultante se recogio por filtracion dando acetato de 5-carbamoil-2-(metilsulfanil)-6-(quinolin-3-ilamino)pirimidin-4-ilo (0,71 g).A mixture of 4-chloro-2- (methylsulfanyl) -6- (quinolin-3-ylamino) pyrimidin-5-carboxamide (Preparation example 344) (0.68 g) and sodium acetate (0.80 g) is DMF added (7 ml) and stirred at 100 ° C for 6 hours. After the reaction liquid returned to room temperature, water was added, and the resulting solid was collected by filtration giving 5-carbamoyl-2- (methylsulfanyl) -6- (quinolin-3-ylamino) pyrimidin-4- acetate ilo (0.71 g).

Ejemplo de preparacion 349Preparation Example 349

A acetato de 5-carbamoil-2-(metilsulfanil)-6-(quinolin-3-ilamino)pirimidin-4-ilo (Ejemplo de preparacion 346) (0,71 g) se anadieron etanol (14 ml) y THF (14 ml), y se anadio hidroxido sodico acuoso 1 M (6 ml) y se agito a temperatura ambiente durante 1 hora. Entonces, se anadio acido clorhfdrico 1 M (6 ml) y el solido precipitado se recogio por filtracion y se seco dando 2-(metilsulfanil)-6-oxo-4-(quinolin-3-ilamino)-1,6-dihidropirimidin-5-carboxamida (0,63 g).To 5-carbamoyl-2- (methylsulfanyl) -6- (quinolin-3-ylamino) pyrimidin-4-yl acetate (Preparation Example 346) (0.71 g) ethanol (14 ml) and THF (14 ml), and 1 M aqueous sodium hydroxide (6 ml) was added and stirred at room temperature for 1 hour. Then, 1M hydrochloric acid (6 ml) was added and the precipitated solid was collected by filtration and dried giving 2- (methylsulfanyl) -6-oxo-4- (quinolin-3-ylamino) -1,6-dihydropyrimidine- 5-carboxamide (0.63 g).

Ejemplo de preparacion 353Preparation Example 353

Se agito una mezcla de 3,5-dicloro-6-etilpirazin-2-carboxamida (600 mg), 3-(metilsulfonil)anilina (467 mg), N,N- diisopropiletilamina (0,48 ml) y dioxano (18 ml) en un tubo cerrado a 170 °C durante 17 horas. Despues de enfriarse, la mezcla se repartio usando acetato de etilo y agua, y la fase organica se lavo con cloruro sodico acuoso saturado y a continuacion se seco sobre sulfato de magnesio anhidro. Despues de separar el disolvente por destilacion, el residuo se lavo con cloroformo, y el solido se recogio por filtracion y se seco dando 5-cloro-6-etil--3-{[3- (metilsulfonil)fenil]amino}pirazin-2-carboxamida (412 mg) como un solido amarillo.A mixture of 3,5-dichloro-6-ethylpyrazin-2-carboxamide (600 mg), 3- (methylsulfonyl) aniline (467 mg), N, N-diisopropylethylamine (0.48 ml) and dioxane (18 ml) was stirred. ) in a closed tube at 170 ° C for 17 hours. After cooling, the mixture was partitioned using ethyl acetate and water, and the organic phase was washed with saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was washed with chloroform, and the solid was collected by filtration and dried to give 5-chloro-6-ethyl-3 - {[3- (methylsulfonyl) phenyl] amino} pyrazine- 2-carboxamide (412 mg) as a yellow solid.

Ejemplo de preparacion 364Preparation Example 364

A una mezcla de 4-cloro-6-[(5-metilpiridin-3-il)amino]-2-(metilsulfanil)pirimidin-5-carboxamida (Ejemplo de preparacion 359) (194 mg) y DMF (5 ml) se anadio acetato sodico (257 mg) y se agito a 100 °C durante 5 horas. Despues de enfriarse el lfquido de reaccion se anadieron acetato de etilo y agua, y el polvo precipitado se recogio por filtracion y se seco dando un solido amarillo claro. A una mezcla del solido, etanol (5 ml), metanol (20 ml) y THFTo a mixture of 4-chloro-6 - [(5-methylpyridin-3-yl) amino] -2- (methylsulfanyl) pyrimidin-5-carboxamide (Preparation Example 359) (194 mg) and DMF (5 ml) Sodium acetate (257 mg) added and stirred at 100 ° C for 5 hours. After cooling the reaction liquid, ethyl acetate and water were added, and the precipitated powder was collected by filtration and dried to give a light yellow solid. To a mixture of solid, ethanol (5 ml), methanol (20 ml) and THF

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(5 ml) se anadio hidroxido sodico acuoso 1 M (3 ml) y se agito a temperatura ambiente durante 1 hora, a 60 °C durante 1 hora y a 80 °C durante 1 hora. Despues de enfriar el ffquido de reaccion, se anadio acido clortffdrico 1 M (3 ml), y el ffquido de reaccion se extrajo con cloroformo-isopropanol. Se anadio gel de sffice a la fase organica, y el disolvente se separo por destilacion, seguido de purificacion por cromatograffa en columna de gel de s^lice (eluyente; cloroformo:metanol = 100:0 a 20:1) dando un producto en bruto. Este producto en bruto se lavo con una pequena cantidad de metanol dando 4-[(5-metilpiridin-3-il)amino]-2-(metilsulfanil)-6-oxo-1,6-dihidropirimidin-5-carboxamida (27 mg) como un solido amarillo.(5 ml) 1 M aqueous sodium hydroxide (3 ml) was added and stirred at room temperature for 1 hour, at 60 ° C for 1 hour and at 80 ° C for 1 hour. After the reaction fluid was cooled, 1 M chloraffric acid (3 ml) was added, and the reaction fluid was extracted with chloroform-isopropanol. Syffice gel was added to the organic phase, and the solvent was distilled off, followed by purification by silica gel column chromatography (eluent; chloroform: methanol = 100: 0 to 20: 1) giving a product in stupid. This crude product was washed with a small amount of methanol giving 4 - [(5-methylpyridin-3-yl) amino] -2- (methylsulfanyl) -6-oxo-1,6-dihydropyrimidine-5-carboxamide (27 mg ) like a yellow solid.

Ejemplo de preparacion 397Preparation Example 397

A una mezcla de 5-cloro-6-etil-3-{[4-(metilsulfanil)fenil]amino}pirazin-2-carboxamida (Ejemplo de preparacion 394) (92 mg) y acido acetico (2,5 ml) se anadieron tungstato de sodio dihidrato (29 mg) y disolucion al 30 % de peroxido de hidrogeno (0,15 ml) y se agito a temperatura ambiente durante 30 minutos. Despues de anadir agua y acetato de etilo al ffquido de reaccion, se anadio hidroxido sodico acuoso 1 M y se agito durante 30 minutos, y el ffquido de reaccion se repartio. Despues de secar sobre sulfato de sodio anhidro, la fase organica se filtro y se concentro. El residuo resultante se lavo con acetato de etilo dando 5-cloro-6-etil-3-{[4-(metilsulfonil)fenil]amino}pirazin-2- carboxamida (103 mg).A mixture of 5-chloro-6-ethyl-3 - {[4- (methylsulfanyl) phenyl] amino} pyrazin-2-carboxamide (Preparation Example 394) (92 mg) and acetic acid (2.5 ml) is they added sodium tungstate dihydrate (29 mg) and 30% solution of hydrogen peroxide (0.15 ml) and stirred at room temperature for 30 minutes. After adding water and ethyl acetate to the reaction fluid, 1 M aqueous sodium hydroxide was added and stirred for 30 minutes, and the reaction fluid was partitioned. After drying over anhydrous sodium sulfate, the organic phase was filtered and concentrated. The resulting residue was washed with ethyl acetate to give 5-chloro-6-ethyl-3 - {[4- (methylsulfonyl) phenyl] amino} pyrazine-2-carboxamide (103 mg).

Ejemplo de preparacion 398Preparation Example 398

A una mezcla de 3,5-dicloro-6-(1-hidroxi-1-metiletil)pirazin-2-carboxamida (2,64 g) y piridina (30 ml) se anadio cloruro de mesilo (2,45 ml) bajo enfriamiento con hielo. Despues de agitar a temperatura ambiente durante 5 horas, la piridina se separo por destilacion a presion reducida, y el residuo resultante se repartio usando acetato de etilo y agua. La fase organica resultante se lavo con 10 % de acido cftrico acuoso, hidrogenocarbonato de sodio acuoso saturado y cloruro sodico acuoso saturado, y se seco sobre sulfato de magnesio anhidro, y el disolvente se separo por destilacion dando un jarabe marron claro. Al jarabe marron claro se anadieron etanol (60 ml) y THF (30 ml), y a continuacion se anadio 10 % de paladio sobre carbono (0,7 g) y se agito a temperatura ambiente durante 14 horas bajo 3 de presion atmosferica de hidrogeno. Despues de la filtracion a traves de Celite, el filtrado se separo por destilacion a presion reducida, y el residuo se diluyo con acetato de etilo y a continuacion se lavo con hidrogenocarbonato de sodio acuoso saturado y cloruro sodico acuoso saturado. Despues de separar el disolvente por destilacion, el residuo se purifico por cromatograffa en columna de gel de sflice (eluyente; cloroformo:metanol = 100:0 a 40:1). El producto en bruto resultante se lavo con eter diisopropflico dando 3,5-di-cloro-6-isopropilpirazin-2- carboxamida (632 mg) como un solido blanco.To a mixture of 3,5-dichloro-6- (1-hydroxy-1-methyl ethyl) pyrazin-2-carboxamide (2.64 g) and pyridine (30 ml) was added mesyl chloride (2.45 ml) under ice cooling After stirring at room temperature for 5 hours, the pyridine was distilled off under reduced pressure, and the resulting residue was partitioned using ethyl acetate and water. The resulting organic phase was washed with 10% aqueous citric acid, saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was distilled off giving a light brown syrup. To the light brown syrup, ethanol (60 ml) and THF (30 ml) were added, then 10% palladium on carbon (0.7 g) was added and stirred at room temperature for 14 hours under 3 atmospheric hydrogen pressure . After filtration through Celite, the filtrate was distilled off under reduced pressure, and the residue was diluted with ethyl acetate and then washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride. After removing the solvent by distillation, the residue was purified by silica gel column chromatography (eluent; chloroform: methanol = 100: 0 to 40: 1). The resulting crude product was washed with diisopropyl ether to give 3,5-di-chloro-6-isopropylpyrazin-2-carboxamide (632 mg) as a white solid.

Ejemplo de preparacion 399Preparation Example 399

A una mezcla de (1-metil-4-oxociclohexil)carbamato de terc-butilo (4,00 g) y metanol (50 ml) se anadieron formiato de amonio (10,2 g) y agua (5 ml) y se agito durante 1 hora hasta que se disolvieron completamente. A continuacion se anadio 10 % de paladio sobre carbono (2,0 g) y se agito a temperatura ambiente durante 65 horas. Despues de separarse los materiales insolubles por filtracion a traves de Celite, el disolvente se separo por destilacion, y se anadio cloroformo al residuo resultante, seguido de secado sobre sulfato de magnesio anhidro. El disolvente se separo por destilacion dando (4-amino-1-metilciclohexil)carbamato de terc-butilo (3,73 g) como un jarabe incoloro.To a mixture of tert-butyl (1-methyl-4-oxocyclohexyl) carbamate (4.00 g) and methanol (50 ml), ammonium formate (10.2 g) and water (5 ml) were added and stirred for 1 hour until completely dissolved. Then 10% palladium on carbon (2.0 g) was added and stirred at room temperature for 65 hours. After insoluble materials were separated by filtration through Celite, the solvent was distilled off, and chloroform was added to the resulting residue, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off giving tert-butyl (4-amino-1-methylcyclohexyl) carbamate (3.73 g) as a colorless syrup.

Ejemplo de preparacion 400Preparation Example 400

A una mezcla de (4-amino-1-metilciclohexil)carbamato de terc-butilo (Ejemplo de preparacion 399) (3,73 g) y etanol (30 ml) se anadio cloruro de hidrogeno 4 M en acetato de etilo (30 ml) bajo enfriamiento con hielo y se agito a temperatura ambiente durante 20 horas. El solido precipitado se recogio por filtracion y se lavo con acetato de etilo dando diclorhidrato de 1-metilciclohexano-1,4-diamino (2,10 g) como un solido blanco.To a mixture of tert-butyl (4-amino-1-methylcyclohexyl) carbamate (Preparation Example 399) (3.73 g) and ethanol (30 ml) 4M hydrogen chloride in ethyl acetate (30 ml) was added ) under ice cooling and stirred at room temperature for 20 hours. The precipitated solid was collected by filtration and washed with ethyl acetate to give 1-methylcyclohexane-1,4-diamino dihydrochloride (2.10 g) as a white solid.

Ejemplo de preparacion 412Preparation Example 412

A una mezcla de 4-(4,4,5,5-tetrametil-1,3,2-dioxaborolan-2-il)-3,6-dihidropiridin-1(2H)-carboxilato de terc-butilo (3,16 g), 4-bromo-3-metoxi-1-nitrobenceno (2,63 g) y DMF (31,6 ml) se anadieron [1,1'- bis(difenilfosfino)ferroceno]dicloropaladio (II), aducto de diclorometano (0,50 g) y carbonato de potasio (4,24 g) y se agito a 80 °C durante 4 horas. Despues de concentrarse esta mezcla a presion reducida se anadieron agua y acetato de etilo, y los materiales insolubles se filtraron a traves de Celite. La fase organica se lavo con cloruro sodico acuoso saturado. Despues de secar sobre sulfato de magnesio anhidro, el disolvente se separo por destilacion, y el residuo se purifico por cromatograffa en columna de gel de sffice (eluyente; n-hexano:acetato de etilo = 1:0 a 2:1) dando 4-(2-metoxi-4-nitrofenil)-3,6-dihidropiridin-1(2H)-carboxilato de terc-butilo (2,21 g) como un solido amarillo.To a mixture of 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3,6-dihydropyridin-1 (2H) tert-butyl carboxylate (3.16 g), 4-Bromo-3-methoxy-1-nitrobenzene (2.63 g) and DMF (31.6 ml) were added [1,1'-bis (diphenylphosphino) ferrocene] dichloropaladium (II), dichloromethane adduct (0.50 g) and potassium carbonate (4.24 g) and stirred at 80 ° C for 4 hours. After concentrating this mixture under reduced pressure, water and ethyl acetate were added, and the insoluble materials were filtered through Celite. The organic phase was washed with saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 1: 0 to 2: 1) giving 4 - (2-Methoxy-4-nitrophenyl) -3,6-dihydropyridin-1 (2H) tert-butyl carboxylate (2.21 g) as a yellow solid.

Ejemplo de preparacion 413Preparation Example 413

A una mezcla de 4-(2-metoxi-4-nitrofenil)-3,6-dihidropiridin-1(2H)-carboxilato de terc-butilo (Ejemplo de preparacion 412) (2,21 g), etanol (40 ml) y THF (20 ml) se anadio 10 % de paladio sobre carbono (1,0 g) y se agito a temperatura ambiente durante 3 horas bajo una atmosfera de hidrogeno a presion normal. Despues de la filtracion a traves deTo a mixture of 4- (2-methoxy-4-nitrophenyl) -3,6-dihydropyridin-1 (2H) tert-butyl carboxylate (Preparation Example 412) (2.21 g), ethanol (40 ml) and THF (20 ml) was added 10% palladium on carbon (1.0 g) and stirred at room temperature for 3 hours under a hydrogen atmosphere at normal pressure. After filtration through

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Celite, el filtrado se separo por destilacion a presion reducida dando 4-(4-amino-2-metoxi-fenil)piperidin-1-carboxilato de terc-butilo (1,97 g) como un solido gris.Celite, the filtrate was distilled off under reduced pressure to give tert-butyl 4- (4-amino-2-methoxy-phenyl) piperidine-1-carboxylate (1.97 g) as a gray solid.

Ejemplo de preparacion 417Preparation Example 417

Se agito una mezcla de 5-cloro-6-(1-hidroxi-1-metiletil)-3-{[4-(4-metilpirazin1-il)fenil]amino}pirazin-2-carboxamida (Ejemplo de preparacion 416) (430 mg) y acido acetico (10 ml) a 120 °C durante 5 horas. Despues de enfriarse el Kquido de reaccion, el disolvente se separo por destilacion, y se anadieron agua e hidrogenocarbonato de sodio acuoso saturado para neutralizar. Despues de la extraccion con acetato de etilo, el extracto se lavo con hidrogenocarbonato de sodio acuoso saturado y cloruro sodico acuoso saturado y se seco sobre sulfato de magnesio anhidro. El disolvente se separo por destilacion, y el residuo se lavo con eter diisopropflico dando 5-cloro- 6-isopropenil-3-{[4-(4-metilpiperazin-1-il)fenil]amino}pirazin-2-carboxamida (265 mg) como un solido naranja.A mixture of 5-chloro-6- (1-hydroxy-1-methyl ethyl) -3 - {[4- (4-methylpyrazin-1-yl) phenyl] amino} pyrazine-2-carboxamide (Preparation Example 416) ( 430 mg) and acetic acid (10 ml) at 120 ° C for 5 hours. After cooling the reaction liquid, the solvent was distilled off, and water and saturated aqueous sodium hydrogen carbonate were added to neutralize. After extraction with ethyl acetate, the extract was washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was washed with diisopropyl ether giving 5-chloro-6-isopropenyl-3 - {[4- (4-methylpiperazin-1-yl) phenyl] amino} pyrazin-2-carboxamide (265 mg) as an orange solid.

Ejemplo de preparacion 430Preparation Example 430

A una mezcla de 7-nitro-2H-1,4-benzoxazin-3(4H)-ona (2,0 g), cloruro de benciltrietilamonio (470 mg), carbonato de potasio (4,27 g) y acetonitrilo (60 ml) se anadio 1-bromo-2-cloroetano (1,28 ml) y se agito a 75 °C durante 3 horas. Despues de enfriarse el lfquido de reaccion, se anadio hidrogenocarbonato de sodio acuoso saturado, y el lfquido de reaccion se extrajo con acetato de etilo y el extracto se lavo con cloruro sodico acuoso saturado. Despues de secar sobre sulfato de magnesio anhidro, el disolvente se separo por destilacion a presion reducida, y el residuo se purifico por cromatograffa en columna de gel de sflice (eluyente: cloroformo) dando 4-(2-cloroetil)-7-nitro-2H-1,4-benzoxazin- 3(4H)-ona (1,92 g) como un polvo amarillo.To a mixture of 7-nitro-2H-1,4-benzoxazin-3 (4H) -one (2.0 g), benzyltriethylammonium chloride (470 mg), potassium carbonate (4.27 g) and acetonitrile (60 ml) 1-Bromo-2-chloroethane (1.28 ml) was added and stirred at 75 ° C for 3 hours. After cooling the reaction liquid, saturated aqueous sodium hydrogen carbonate was added, and the reaction liquid was extracted with ethyl acetate and the extract was washed with saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform) to give 4- (2-chloroethyl) -7-nitro- 2H-1,4-benzoxazin-3 (4H) -one (1.92 g) as a yellow powder.

Ejemplo de preparacion 432Preparation Example 432

A una mezcla de 4-(2-cloroetil)-7-nitro-2H-1,4-benzoxazin-3(4H)-ona (Ejemplo de preparacion 430) (1,08 g), carbonato de potasio (0,87 g) y acetonitrilo (10,8 ml) se anadio 1-metilpiperazina (1,39 ml) y se agito a 80 °C durante 48 horas. Despues de enfriarse el lfquido de reaccion, se anadio hidrogenocarbonato de sodio acuoso saturado, y el lfquido de reaccion se extrajo con acetato de etilo y el extracto se lavo con cloruro sodico acuoso saturado. Despues de secar sobre sulfato de magnesio anhidro, el disolvente se separo por destilacion a presion reducida, y el residuo se purifico por cromatograffa en columna de gel de sflice (eluyente; cloroformo:metanol = 100:0 a 20:1) dando 4-[2- (4-metilpiperazin-1-il)etil]-7-nitro-2H-1,4-benzoxazin-3(4H)-ona (690 mg) como un lfquido amarillo.To a mixture of 4- (2-Chloroethyl) -7-nitro-2H-1,4-benzoxazin-3 (4H) -one (Preparation Example 430) (1.08 g), potassium carbonate (0.87 g) and acetonitrile (10.8 ml) 1-methylpiperazine (1.39 ml) was added and stirred at 80 ° C for 48 hours. After cooling the reaction liquid, saturated aqueous sodium hydrogen carbonate was added, and the reaction liquid was extracted with ethyl acetate and the extract was washed with saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; chloroform: methanol = 100: 0 to 20: 1) giving 4- [2- (4-Methylpiperazin-1-yl) ethyl] -7-nitro-2H-1,4-benzoxazin-3 (4H) -one (690 mg) as a yellow liquid.

Ejemplo de preparacion 440Preparation Example 440

Una mezcla de 3,5-dicloro-6-(1-hidroxi-1-metiletil)pirazin-2-carboxamida (1,10 g), 4-[4-(4-metilpiperazin-1-il)piperidin- 1-il]-3-(trifluorometil)anilina (Ejemplo de preparacion 436) (1,58 g), N,N-diisopropiletilamina (0,80 ml) y dioxano (31 ml) se agito a 100 °C durante 135 horas. Despues de enfriarse, se anadio agua, seguido de extraccion con acetato de etilo. Ademas, los materiales insolubles se separaron por filtracion, y los materiales insolubles se disolvieron en metanol y a partir de aqrn se mezclaron con la fase organica. El disolvente se separo por destilacion a presion reducida, seguido de secado dando un solido marron. Una mezcla del solido marron y acido acetico (30 ml) se agito a 120 °C durante 5 horas. Despues de separarse el disolvente por destilacion, se anadio hidrogenocarbonato de sodio acuoso saturado, y el solido precipitado se recogio por filtracion y se lavo con agua. El solido resultante se purifico por cromatograffa en columna de gel de sflice basica (eluyente: cloroformo) dando 5-cloro-6-isopropenil-3- ({4-[4-(4-metilpiperazin-1-il)piperidin-1-il]-3-(trifluorometil)fenil}amino)pirazin-2-carboxamida (0,99 g) como un solido amarillo.A mixture of 3,5-dichloro-6- (1-hydroxy-1-methyl ethyl) pyrazin-2-carboxamide (1.10 g), 4- [4- (4-methylpiperazin-1-yl) piperidine-1- il] -3- (trifluoromethyl) aniline (Preparation Example 436) (1.58 g), N, N-diisopropylethylamine (0.80 ml) and dioxane (31 ml) was stirred at 100 ° C for 135 hours. After cooling, water was added, followed by extraction with ethyl acetate. In addition, insoluble materials were filtered off, and insoluble materials were dissolved in methanol and then mixed with the organic phase. The solvent was distilled off under reduced pressure, followed by drying giving a brown solid. A mixture of the brown solid and acetic acid (30 ml) was stirred at 120 ° C for 5 hours. After the solvent was distilled off, saturated aqueous sodium hydrogen carbonate was added, and the precipitated solid was collected by filtration and washed with water. The resulting solid was purified by basic silica gel column chromatography (eluent: chloroform) to give 5-chloro-6-isopropenyl-3- ({4- [4- (4-methylpiperazin-1-yl) piperidin-1- il] -3- (trifluoromethyl) phenyl} amino) pyrazin-2-carboxamide (0.99 g) as a yellow solid.

Ejemplo de preparacion 444Preparation Example 444

Despues de agitar una mezcla de acetato de paladio (188 mg), 1,1'-binaftaleno-2,2'-diilbis(difenilfosfina) (781 mg), carbonato de cesio (4,09 g) y THF (20 ml) durante 30 minutos, se anadio una mezcla de 1-bromo-3-metoxi-5- nitrobenceno (1,94 g), 1-metilpiperazina (2,76 ml) y THF (20 ml) y se calento a reflujo durante 14 horas. Despues de enfriarse, el lfquido de reaccion se diluyo con acetato de etilo, y los materiales insolubles se separaron por filtracion. Despues de la extraccion con acido clorlffdrico 2 M del filtrado, la fase acuosa resultante se basifico con 50 % de hidroxido potasico acuoso y a continuacion se extrajo con cloroformo. Despues de secar la fase organica sobre sulfato de magnesio anhidro, el disolvente se separo por destilacion, y el residuo se purifico por cromatograffa en columna de gel de sflice (eluyente; cloroformo:metanol = 100:0 a 20:1) dando 1-(3-metoxi-5-nitrofenil)-4- metilpiperazina (1,01 g) como un jarabe naranja.After stirring a mixture of palladium acetate (188 mg), 1,1'-binaphthalene-2,2'-diylbis (diphenylphosphine) (781 mg), cesium carbonate (4.09 g) and THF (20 ml) for 30 minutes, a mixture of 1-bromo-3-methoxy-5- nitrobenzene (1.94 g), 1-methylpiperazine (2.76 ml) and THF (20 ml) was added and heated at reflux for 14 hours . After cooling, the reaction liquid was diluted with ethyl acetate, and the insoluble materials were filtered off. After the extraction with 2M hydrochloric acid of the filtrate, the resulting aqueous phase was basified with 50% aqueous potassium hydroxide and then extracted with chloroform. After drying the organic phase over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent; chloroform: methanol = 100: 0 to 20: 1) giving 1- (3-Methoxy-5-nitrophenyl) -4-methylpiperazine (1.01 g) as an orange syrup.

Ejemplo de preparacion 454Preparation Example 454

A una mezcla de 4-(4-amino-2-metoxi-fenil)piperidin-1-carboxilato de terc-butilo (Ejemplo de preparacion 413) (4,25 g) y THF (100 ml) se anadieron hidrogenocarbonato de sodio (1,28 g) y agua (30 ml), seguido de la adicion gota a gota de cloroformiato de bencilo (1,98 ml) bajo enfriamiento con hielo y agitacion durante la noche. Despues de la adicion de agua y extraccion con acetato de etilo, el extracto se lavo con cloruro sodico acuoso saturado. Despues de secar sobre sulfato de magnesio anhidro, el disolvente se separo por destilacion, y el residuo se purifico porTo a mixture of tert-butyl 4- (4-amino-2-methoxy-phenyl) piperidin-1-carboxylate (Preparation Example 413) (4.25 g) and THF (100 ml) were added sodium hydrogen carbonate ( 1.28 g) and water (30 ml), followed by the dropwise addition of benzyl chloroformate (1.98 ml) under ice cooling and stirring overnight. After the addition of water and extraction with ethyl acetate, the extract was washed with saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by

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cromatograffa en columna de gel de sffice (eluyente; n-hexano:acetato de etilo = 2:1) dando 4-(4- {[(benciloxi)carbonil]amino}-2-metoxifenil)piperidin-1-carboxilato de terc-butilo (4,92 g) como un amorfo incoloro.Sffice gel column chromatography (eluent; n-hexane: ethyl acetate = 2: 1) giving 4- (4- {[(benzyloxy) carbonyl] amino} -2-methoxyphenyl) piperidine-1-carboxylate tertiary butyl (4.92 g) as a colorless amorphous.

Ejemplo de preparacion 455Preparation Example 455

Una mezcla de 4-(4-{[(benciloxi)carbonil]amino}-2-metoxifenil)piperidin-1-carboxilato de terc-butilo (Ejemplo de preparacion 454) (4,92 g), acido trifluoroacetico (10 ml) y 1,2-dicloroetano (50 ml) se agito a temperatura ambiente durante 1 hora. El disolvente de reaccion se concentro a presion reducida, y despues de la adicion de hidrogenocarbonato de sodio acuoso saturado, el residuo se extrajo con cloroformo. Despues de secar sobre sulfato de magnesio anhidro, el disolvente se separo por destilacion, y el residuo se solidifico por la adicion de eter dietffico dando (3-metoxi-4-piperidin-4-ilfenil)carbamato de bencilo (3,24 g) como un solido blanco.A mixture of tert-butyl 4- (4 - {[(benzyloxy) carbonyl] amino} -2-methoxyphenyl) piperidine-1-carboxylate (Preparation Example 454) (4.92 g), trifluoroacetic acid (10 ml) and 1,2-dichloroethane (50 ml) was stirred at room temperature for 1 hour. The reaction solvent was concentrated under reduced pressure, and after the addition of saturated aqueous sodium hydrogen carbonate, the residue was extracted with chloroform. After drying over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was solidified by the addition of diethyl ether giving benzyl (3-methoxy-4-piperidin-4-ylphenyl) carbamate (3.24 g) Like a white solid

Ejemplo de preparacion 464Preparation Example 464

A una mezcla de (3-metoxi-4-piperidin-4-ilfenil)carbamato de bencilo (Ejemplo de preparacion 455) (1,52 g) y 1,2- dicloroetano (70 ml) se anadieron formalina (3,62 ml) y triacetoxiborohidruro de sodio (1,42 g) y se agito durante la noche a temperatura ambiente. Despues de la adicion de agua e hidrogenocarbonato de sodio acuoso saturado, el ffquido de reaccion se extrajo con cloroformo y se seco la fase organica sobre sulfato de magnesio anhidro. Despues de separarse el disolvente por destilacion a presion reducida, el residuo se purifico por cromatograffa en columna de gel de sffice (eluyente; cloroformo:metanol:amoniaco acuoso saturado = 100:0:0 a 10:1:0,1) dando [3-metoxi-4-(1- metilpiperidin-4-il)fenil]carbamato de bencilo (1,26 g) como un solido blanco.To a mixture of benzyl (3-methoxy-4-piperidin-4-ylphenyl) carbamate (Preparation example 455) (1.52 g) and 1,2-dichloroethane (70 ml), formalin (3.62 ml) was added ) and sodium triacetoxyborohydride (1.42 g) and stirred overnight at room temperature. After the addition of water and saturated aqueous sodium hydrogen carbonate, the reaction fluid was extracted with chloroform and the organic phase was dried over anhydrous magnesium sulfate. After the solvent was removed by distillation under reduced pressure, the residue was purified by silica gel column chromatography (eluent; chloroform: methanol: saturated aqueous ammonia = 100: 0: 0 to 10: 1: 0.1) giving [ Benzyl 3-methoxy-4- (1- methylpiperidin-4-yl) phenyl] carbamate (1.26 g) as a white solid.

Ejemplo de preparacion 467Preparation Example 467

A una mezcla de 7-amino-4-[3-(4-metilpiperazin-1-il)propil]-2H-1,4-benzoxazin-3(4H)-ona (Ejemplo de preparacion 435) (300 mg) y THF (9 ml) se realizo la adicion gota a gota gradual de complejo de borano-tetrahidrofurano (3,0 ml, disolucion 1 M de THF) bajo enfriamiento con hielo bajo una atmosfera de argon. Despues de completarse la adicion gota a gota, la mezcla se agito a temperatura ambiente durante 1 hora y se agito adicionalmente a 70 °C durante 3 horas. Despues de anadirse gradualmente metanol (10 ml) al ffquido de reaccion bajo enfriamiento con hielo, se anadieron acido clorhfdrico 1 M (5 ml) y despues de hidroxido sodico acuoso 1 M (10 ml) y se agito a temperatura ambiente durante 1 hora. Despues de la dilucion con agua, el ffquido de reaccion se extrajo con acetato de etilo. Despues de separarse el disolvente por destilacion, el residuo se purifico por cromatograffa en columna de gel de sffice (eluyente; cloroformo :metanol = 100:0 a 20:1) dando 4-[3-(4-metilpiperazin-1-il)propil]-3,4-dihidro-2H-1,4- benzoxazin-7-amina (120 mg).To a mixture of 7-amino-4- [3- (4-methylpiperazin-1-yl) propyl] -2H-1,4-benzoxazin-3 (4H) -one (Preparation Example 435) (300 mg) and THF (9 ml) was made the gradual dropwise addition of borane-tetrahydrofuran complex (3.0 ml, 1 M solution of THF) under ice cooling under an argon atmosphere. After completion of the dropwise addition, the mixture was stirred at room temperature for 1 hour and further stirred at 70 ° C for 3 hours. After gradually adding methanol (10 ml) to the reaction fluid under ice cooling, 1 M hydrochloric acid (5 ml) was added and after 1 M aqueous sodium hydroxide (10 ml) and stirred at room temperature for 1 hour. After dilution with water, the reaction fluid was extracted with ethyl acetate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (eluent; chloroform: methanol = 100: 0 to 20: 1) to give 4- [3- (4-methylpiperazin-1-yl) propyl] -3,4-dihydro-2H-1,4-benzoxazin-7-amine (120 mg).

Ejemplo de preparacion 468Preparation Example 468

A una mezcla de [3-metoxi-4-(1-metilpiperidin-4-il)fenil]carbamato de bencilo (Ejemplo de preparacion 464) (1,26 g), etanol (20 ml) y THF (10 ml) se anadio 5% de paladio sobre carbono (0,38 g) y se agito durante la noche a temperatura ambiente bajo una atmosfera de hidrogeno a presion normal. Despues de la filtracion a traves de Celite, el filtrado se separo por destilacion a presion reducida dando 3-metoxi-4-(1-metilpiperidin-4-il)anilina (0,80 g) como un solido rosa claro.To a mixture of benzyl [3-methoxy-4- (1-methylpiperidin-4-yl) phenyl] carbamate (Preparation Example 464) (1.26 g), ethanol (20 ml) and THF (10 ml) Add 5% palladium on carbon (0.38 g) and stir overnight at room temperature under a hydrogen atmosphere at normal pressure. After filtration through Celite, the filtrate was distilled off under reduced pressure to give 3-methoxy-4- (1-methylpiperidin-4-yl) aniline (0.80 g) as a light pink solid.

Ejemplo de preparacion 472Preparation Example 472

A una mezcla de 2-[metil(3-nitrofenil)amino]etanol (780 mg) y diclorometano (20 ml) se anadieron secuencialmente trietilamina (0,66 ml) y cloruro de mesilo (0,37 ml) bajo enfriamiento con hielo y se agito durante 3 horas. Se anadio agua al ffquido de reaccion, y la fase organica se separo y se lavo con cloruro sodico acuoso saturado. Despues de secar sobre sulfato de magnesio anhidro, el disolvente se separo por destilacion dando metanosulfonato de 2- [metil(3-nitrofenil)amino]etilo (1,0 g) como un solido amarillo.To a mixture of 2- [methyl (3-nitrophenyl) amino] ethanol (780 mg) and dichloromethane (20 ml), triethylamine (0.66 ml) and mesyl chloride (0.37 ml) were sequentially added under ice cooling and stirred for 3 hours. Water was added to the reaction fluid, and the organic phase was separated and washed with saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent was distilled off to give 2- [methyl (3-nitrophenyl) amino] ethyl methanesulfonate (1.0 g) as a yellow solid.

Ejemplo de preparacion 473Preparation Example 473

Se hizo reaccionar una mezcla de metanosulfonato de 2-[metil(3-nitrofenil)amino]etilo (Ejemplo de preparacion 472) (1,0 g), 1-metilpiperazina (1,61 ml) y NMP (5 ml) a 130 °C durante 30 minutos usando un sistema de reaccion de microondas. El ffquido de reaccion se diluyo con agua, se extrajo con un disolvente mixto de cloroformo y metanol (10:1) y a continuacion se lavo con cloruro sodico acuoso saturado. Despues de secar sobre sulfato de magnesio anhidro, el disolvente se separo por destilacion, y el residuo se purifico por cromatograffa en columna de gel de sffice (eluyente; cloroformo:metanol:amoniaco acuoso saturado = 10:1:0,1) dando N-metil-N-[2-(4-metilpiperazin-1-il)etil]-3- nitroanilina (890 mg) como un aceite amarillo.A mixture of 2- [methyl (3-nitrophenyl) amino] ethyl methanesulfonate (Preparation Example 472) (1.0 g), 1-methylpiperazine (1.61 ml) and NMP (5 ml) was reacted at 130 ° C for 30 minutes using a microwave reaction system. The reaction fluid was diluted with water, extracted with a mixed solvent of chloroform and methanol (10: 1) and then washed with saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by sffice gel column chromatography (eluent; chloroform: methanol: saturated aqueous ammonia = 10: 1: 0.1) giving N -methyl-N- [2- (4-methylpiperazin-1-yl) ethyl] -3-nitroaniline (890 mg) as a yellow oil.

Ejemplo de preparacion 502Preparation Example 502

A una mezcla de 8-(2-metoxi-5-nitrofenil)-1,4-dioxa-8-azaespiro[4.5]decano (Ejemplo de preparacion 495) (795 mg) y dioxano (16 ml) se anadio acido clorhfdrico 4 M (6,8 ml) y se agito durante la noche a 80 °C. El ffquido de reaccion se concentro a presion reducida, y se anadio hidrogenocarbonato de sodio acuoso saturado al concentrado. ElTo a mixture of 8- (2-methoxy-5-nitrophenyl) -1,4-dioxa-8-azaspiro [4.5] decane (Preparation example 495) (795 mg) and dioxane (16 ml) was added hydrochloric acid 4 M (6.8 ml) and stirred overnight at 80 ° C. The reaction fluid was concentrated under reduced pressure, and saturated aqueous sodium hydrogen carbonate was added to the concentrate. He

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concentrado se extrajo con cloroformo y a continuacion se lavo con cloruro sodico acuoso saturado. Despues de secar sobre sulfato de sodio anhidro, el disolvente se separo por destilacion a presion reducida, y el residuo se purifico por cromatograffa en columna de gel de s^lice (eluyente; acetato de etilo:n-hexano) dando 1-(2-metoxi-5- nitrofenil)piperidin-4-ona (296 mg).Concentrate was extracted with chloroform and then washed with saturated aqueous sodium chloride. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate: n-hexane) giving 1- (2 -methoxy-5- nitrophenyl) piperidin-4-one (296 mg).

Ejemplo de preparacion 503Preparation Example 503

A una mezcla de 1-(2-metoxi-5-nitrofenil)piperidin-4-ona (Ejemplo de preparacion 502) (296 mg), 1-metilpiperazina (0,20 ml) y 1,2-dicloroetano (11 ml) se anadio triacetoxiborohidruro de sodio (385 mg) y se agito durante la noche a temperature ambiente. Despues de la adicion de agua e hidrogenocarbonato de sodio acuoso saturado, el lfquido de reaccion se extrajo con cloroformo, y se seco la fase organica sobre sulfato de sodio anhidro. El disolvente se separo por destilacion a presion reducida, y el residuo se purifico por cromatograffa en columna de gel de sflice (eluyente: cloroformo: metanol =100:0 a 10:1) dando 1-[1-(2-metoxi-5-nitrofenil)piperidin-4-il]-4-metilpiperazina (dfa g) como un aceite marron.To a mixture of 1- (2-methoxy-5-nitrophenyl) piperidin-4-one (Preparation example 502) (296 mg), 1-methylpiperazine (0.20 ml) and 1,2-dichloroethane (11 ml) sodium triacetoxyborohydride (385 mg) was added and stirred overnight at room temperature. After the addition of water and saturated aqueous sodium hydrogen carbonate, the reaction liquid was extracted with chloroform, and the organic phase was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform: methanol = 100: 0 to 10: 1) giving 1- [1- (2-methoxy-5 -nitrophenyl) piperidin-4-yl] -4-methylpiperazine (dfa g) as a brown oil.

Ejemplo de preparacion 516Preparation Example 516

A una mezcla de 1-fluoro-2-metil-4-nitrobenceno (3,0 g), carbonato de potasio (5,35 g) y DMF (30 ml) se anadio 1,4- dioxa-8-azaespiro[4.5]decano (4,15 g) y se agito a 80 °C durante 20 horas. Despues de enfriarse, el lfquido de reaccion se diluyo con acetato de etilo y se lavo con agua y cloruro sodico acuoso saturado. Despues de secar sobre sulfato de magnesio anhidro, el disolvente se separo por destilacion, y el residuo se purifico por cromatograffa en columna de gel de sflice (eluyente; cloroformo:metanol =100:0 a 100:1) dando 8-(2-metil-4-nitrofenil)-1,4-dioxa-8- azaespiro[4.5]decano (5,13 g) como un solido amarillo.To a mixture of 1-fluoro-2-methyl-4-nitrobenzene (3.0 g), potassium carbonate (5.35 g) and DMF (30 ml) was added 1,4-dioxa-8-azaespiro [4.5 ] decane (4.15 g) and stirred at 80 ° C for 20 hours. After cooling, the reaction liquid was diluted with ethyl acetate and washed with water and saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent; chloroform: methanol = 100: 0 to 100: 1) giving 8- (2- methyl-4-nitrophenyl) -1,4-dioxa-8-azaespiro [4.5] decane (5.13 g) as a yellow solid.

Ejemplo de preparacion 545Preparation Example 545

A una mezcla de 5-cloro-6-(2-hidroxipropan-2-il)-3-([3-metoxi-4-(4-metilpiperazin-1-il)fenil]amino}pirazin-2-To a mixture of 5-chloro-6- (2-hydroxypropan-2-yl) -3 - ([3-methoxy-4- (4-methylpiperazin-1-yl) phenyl] amino} pyrazine-2-

carboxamida (Ejemplo de preparacion 544) (300 mg) y acido trifluoroacetico (3 ml) se anadio trietilsilano (0,55 ml) bajo enfriamiento con hielo y se agito bajo enfriamiento con hielo durante 10 minutos y a temperatura ambiente durante 22 horas. Despues de concentrarse el ffquido de reaccion, el residuo se diluyo con cloroformo y se lavo con hidrogenocarbonato de sodio acuoso saturado. Despues de secar sobre sulfato de magnesio anhidro, el disolvente se separo por destilacion, y el residuo se purifico por cromatograffa en columna de gel de sflice (eluyente; cloroformo:metanol:amoniaco acuoso saturado=100:0:0 a 20:1:0,1) dando un producto en bruto. El producto en bruto se lavo con eter diisopropflico dando 5-cloro-6-isopropil-3-{[3-metoxi-4-(4-metilpiperazin-1-il)fenil]amino}pirazin-2- carboxamida (219 mg) como un solido naranja.Carboxamide (Preparation Example 544) (300 mg) and trifluoroacetic acid (3 ml) triethylsilane (0.55 ml) was added under ice cooling and stirred under ice cooling for 10 minutes and at room temperature for 22 hours. After the reaction fluid was concentrated, the residue was diluted with chloroform and washed with saturated aqueous sodium hydrogen carbonate. After drying over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent; chloroform: methanol: saturated aqueous ammonia = 100: 0: 0 to 20: 1: 0.1) giving a raw product. The crude product was washed with diisopropyl ether giving 5-chloro-6-isopropyl-3 - {[3-methoxy-4- (4-methylpiperazin-1-yl) phenyl] amino} pyrazine-2-carboxamide (219 mg) Like a solid orange

La Tablas 7 a 47 muestran las estructuras qmmicas de los compuestos preparados en los ejemplos de preparacion anteriores, y las estructuras qmmicas de los compuestos de ejemplos de preparacion preparados del mismo modo que se muestra en los ejemplos de preparacion anteriores usando materiales de partida correspondientes. Las Tablas 48 a 84 muestran los procesos de preparacion y datos ffsicos y qmmicos de estos ejemplos de compuestos de preparacion.Tables 7 to 47 show the chemical structures of the compounds prepared in the previous preparation examples, and the chemical structures of the compounds of preparation examples prepared in the same manner as shown in the previous preparation examples using corresponding starting materials. Tables 48 to 84 show the preparation processes and physical and chemical data of these examples of preparation compounds.

Ejemplo 4Example 4

Se calento una mezcla de 4-{[2-(isopropilsulfonil)fenil]amino}-2-(metilsulfanil)-6-oxo-1,6-dihidropirimidin-5-A mixture of 4 - {[2- (isopropylsulfonyl) phenyl] amino} -2- (methylsulfanyl) -6-oxo-1,6-dihydropyrimidin-5- was heated

carboxamida (Ejemplo de preparacion 294) (200 mg), 1-(aminometil)-N,N-dimetilciclohexilamina (409 mg) y NMP (1 ml) a 180 °C durante 10 minutos usando un sistema de reaccion de microondas. Despues de enfriarse, el lfquido de reaccion se diluyo con acetato de etilo, y el cristal precipitado se recogio por filtracion y se lavo con acetato de etilo dando un solido blanco. Al solido blanco se anadio un disolvente mixto de etanol y agua, se calento y a continuacion se enfrio, y el solido precipitado se recogio por filtracion dando 2-({[1-(dimetilamino)ciclohexil]metil}amino)-4-{[2- (isopropilsulfonil)fenil]amino}-6-oxo-1,6-dihidropirimidin-5-carboxamida (136 mg) como un solido blanco.Carboxamide (Preparation Example 294) (200 mg), 1- (aminomethyl) -N, N-dimethylcyclohexylamine (409 mg) and NMP (1 ml) at 180 ° C for 10 minutes using a microwave reaction system. After cooling, the reaction liquid was diluted with ethyl acetate, and the precipitated crystal was collected by filtration and washed with ethyl acetate to give a white solid. A mixed solvent of ethanol and water was added to the white solid, heated and then cooled, and the precipitated solid was collected by filtration giving 2 - ({[1- (dimethylamino) cyclohexyl] methyl} amino) -4 - {[ 2- (Isopropylsulfonyl) phenyl] amino} -6-oxo-1,6-dihydropyrimidin-5-carboxamide (136 mg) as a white solid.

Ejemplo 19Example 19

Se calento una mezcla de 4-{[2-(isopropilsulfonil)fenil]amino}-2-(metilsulfanil)-6-oxo-1,6-dihidropirimidin-5-A mixture of 4 - {[2- (isopropylsulfonyl) phenyl] amino} -2- (methylsulfanyl) -6-oxo-1,6-dihydropyrimidin-5- was heated

carboxamida (Ejemplo de preparacion 294) (200 mg), 2-(aminometil)piperidin-1-carboxilato de terc-butilo (1,12 g) y NMP (1 ml) a 180 °C durante 10 minutos usando un sistema de reaccion de microondas. Despues de enfriarse, el lfquido de reaccion se diluyo con acetato de etilo y se lavo con agua y cloruro sodico acuoso saturado. Despues de secar sobre sulfato de magnesio anhidro, el disolvente se separo por destilacion, y el residuo se purifico por cromatograffa en columna de gel de sflice (cloroformo:metanol = 100:0 a 20:1) dando un amorfo blanco. A una mezcla del amorfo blanco se anadio acetato de etilo (10 ml) y etanol (5 ml), cloruro de hidrogeno 4 M en acetato de etilo (5 ml) bajo enfriamiento con hielo y se agito a temperatura ambiente durante 4 horas. El solido precipitado se recogio por filtracion y se seco dando clorhidrato de 4-{[2-(isopropilsulfonil)fenil]amino}-6-oxo-2-[(piperidin-2- ilmetil)amino]-1,6-dihidropirimidin-5-carboxamida (126 mg) como un solido blanco.carboxamide (Preparation Example 294) (200 mg), tert-butyl 2- (aminomethyl) piperidin-1-carboxylate (1.12 g) and NMP (1 ml) at 180 ° C for 10 minutes using a reaction system of microwave. After cooling, the reaction liquid was diluted with ethyl acetate and washed with water and saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform: methanol = 100: 0 to 20: 1) to give a white amorphous. To a mixture of the white amorphous was added ethyl acetate (10 ml) and ethanol (5 ml), 4M hydrogen chloride in ethyl acetate (5 ml) under ice cooling and stirred at room temperature for 4 hours. The precipitated solid was collected by filtration and dried to give 4 - {[2- (isopropylsulfonyl) phenyl] amino} -6-oxo-2 - [(piperidin-2-ylmethyl) amino] -1,6-dihydropyrimidine hydrochloride 5-carboxamide (126 mg) as a white solid.

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Ejemplo 29Example 29

A una mezcla de 3-[(5-carbamoil-4-{[2-(isopropilsulfonil)fenil]amino}-6-oxo-1,6-dihidropirimidin-2-il)amino]piperidin-1- carboxilato de terc-butilo (Ejemplo 28) (299 mg) y acetato de etilo (3 ml) se anadio cloruro de hidrogeno 4 M en acetato de etilo (2,7 ml) bajo enfriamiento con hielo y se agito a temperatura ambiente durante 1 hora. El solido precipitado se recogio por filtracion y se seco dando diclorhidrato de 4-{[2-(isopropilsulfonil)fenil]amino}-6-oxo-2- (piperidin-3-ilamino)-1,6-dihidropirimidin-5-carboxamida (194 mg) como un solido blanco.To a mixture of 3 - [(5-carbamoyl-4 - {[2- (isopropylsulfonyl) phenyl] amino} -6-oxo-1,6-dihydropyrimidin-2-yl) amino] piperidine-1-carboxylate tertiary Butyl (Example 28) (299 mg) and ethyl acetate (3 ml) 4M hydrogen chloride in ethyl acetate (2.7 ml) was added under ice cooling and stirred at room temperature for 1 hour. The precipitated solid was collected by filtration and dried to give 4 - {[2- (isopropylsulfonyl) phenyl] amino} -6-oxo-2- (piperidin-3-ylamino) -1,6-dihydropyrimidine-5-carboxamide dihydrochloride. (194 mg) as a white solid.

Ejemplo 31Example 31

A una mezcla de diclorhidrato de 4-{[2-(isopropilsulfonil)fenil]amino}-6-oxo-2-(piperidin-3-ilamino)-1,6-dihidropirimidin- 5-carboxamida (Ejemplo 29) (67 mg) y piridina (1,3 ml) se anadio cloruro de mesilo (0,10 ml) bajo enfriamiento con hielo y se agito durante 1 hora. Despues de anadir etanol al sistema de reaccion, el sistema de reaccion se concentro. El residuo resultante se repartio usando cloroformo e hidrogenocarbonato de sodio acuoso saturado, y la fase organica se seco. La fase organica se concentro, seguido de un proceso azeotropico con tolueno. El residuo resultante se solidifico con acetato de etilo-hexano. El solido resultante se recristalizo en etanol dando 4-{[2- (isopropilsulfonil)fenil]amino}-2-{[1-(metilsulfonil)piperidin-3-il]amino}-6-oxo-1,6-dihidropirimidin-5-carboxamida (43 mg).To a mixture of 4 - {[2- (isopropylsulfonyl) phenyl] amino} -6-oxo-2- (piperidin-3-ylamino) -1,6-dihydropyrimidine-5-carboxamide dihydrochloride (Example 29) (67 mg) ) and pyridine (1.3 ml), mesyl chloride (0.10 ml) was added under ice cooling and stirred for 1 hour. After adding ethanol to the reaction system, the reaction system was concentrated. The resulting residue was partitioned using chloroform and saturated aqueous sodium hydrogen carbonate, and the organic phase was dried. The organic phase was concentrated, followed by an azeotropic process with toluene. The resulting residue was solidified with ethyl acetate-hexane. The resulting solid was recrystallized from ethanol giving 4 - {[2- (isopropylsulfonyl) phenyl] amino} -2 - {[1- (methylsulfonyl) piperidin-3-yl] amino} -6-oxo-1,6-dihydropyrimidine- 5-carboxamide (43 mg).

Ejemplo 37Example 37

Una mezcla de 4-{[3-(metilcarbamoil)fenil]amino}-2-(metilsulfinil)-6-oxo-1,6-dihidropirimidin-5-carboxamida (Ejemplo de preparacion 311) (234 mg), 1-(aminometil)ciclohexanoamina (172 mg) y NMP (2 ml) se agito a 80 °C durante 30 minutos. Despues de enfriarse, el lfquido de reaccion se diluyo con acetato de etilo, y el solido precipitado se recogio por filtracion. Este solido se calento con etanol-agua y se lavo dando 2-{[(1-aminociclohexil)metil]amino}-4-{[3- (metilcarbamoil)fenil]amino}-6-oxo-1,6-dihidropirimidin-5-carboxamida (215 mg) como un solido blanco.A mixture of 4 - {[3- (methylcarbamoyl) phenyl] amino} -2- (methylsulfinyl) -6-oxo-1,6-dihydropyrimidin-5-carboxamide (Preparation Example 311) (234 mg), 1- ( aminomethyl) cyclohexanoamine (172 mg) and NMP (2 ml) was stirred at 80 ° C for 30 minutes. After cooling, the reaction liquid was diluted with ethyl acetate, and the precipitated solid was collected by filtration. This solid was heated with ethanol-water and washed giving 2 - {[(1-aminocyclohexyl) methyl] amino} -4 - {[3- (methylcarbamoyl) phenyl] amino} -6-oxo-1,6-dihydropyrimidine- 5-carboxamide (215 mg) as a white solid.

Ejemplo 84Example 84

Se calento una mezcla de 5-cloro-6-etil-3-{[3-(metilsulfonil)fenil]amino}pirazin-2-carboxamida (Ejemplo de preparacion 353) (150 mg), 1-(aminometil)ciclohexanoamina (163 mg) y NMP (1 ml) a 180 °C durante 20 minutos usando un sistema de reaccion de microondas. El lfquido de reaccion se enfrio, y se anadieron acetato de etilo y agua y se agitaron durante 30 minutos. A partir de aqrn, el polvo precipitado se recogio por filtracion. Este polvo se calento con etanol-agua (1:1) y se lavo dando 5-{[(1-aminociclohexil)metil]amino}-6-etil-3-{[3- (metilsulfonil)fenil]amino}pirazin-2-carboxamida (112 mg) como un solido blanco.A mixture of 5-chloro-6-ethyl-3 - {[3- (methylsulfonyl) phenyl] amino} pyrazin-2-carboxamide (Preparation Example 353) (150 mg), 1- (aminomethyl) cyclohexanoamine (163) was heated. mg) and NMP (1 ml) at 180 ° C for 20 minutes using a microwave reaction system. The reaction liquid was cooled, and ethyl acetate and water were added and stirred for 30 minutes. From here, the precipitated powder was collected by filtration. This powder was heated with ethanol-water (1: 1) and washed giving 5 - {[(1-aminocyclohexyl) methyl] amino} -6-ethyl-3 - {[3- (methylsulfonyl) phenyl] amino} pyrazine- 2-carboxamide (112 mg) as a white solid.

Ejemplo 146Example 146

Se agito una mezcla de 3,5-dicloro-6-etilpirazin-2-carboxamida (200 mg), 3-cloro-4-metilsulfonilanilina (374 mg) y NMP (1 ml) a 230 °C durante 1 hora usando un sistema de reaccion de microondas. A partir de aqrn, se anadio trans-4-aminociclohexanol (524 mg) al lfquido de reaccion y se agito a 190 °C durante 30 minutos usando un sistema de reaccion de microondas. Despues de enfriarse, el lfquido de reaccion se repartio usando acetato de etilo y agua, y la fase organica se lavo con hidrogenocarbonato de sodio acuoso saturado y cloruro sodico acuoso saturado. Despues de secar sobre sulfato de magnesio anhidro, el disolvente se separo por destilacion, y el residuo se purifico por cromatograffa en columna de gel de sflice (eluyente; cloroformo:metanol = 10:0 a 30:1) dando un producto en bruto. Este producto se calento con etanol y se lavo dando un solido amarillo claro. Al solido amarillo claro se anadio acetato de etilo y se calento, y los materiales insolubles se separaron por filtracion y el filtrado se concentro. Despues de concentrar el filtrado, el residuo se calento y se lavo con etanol dando 3-{[3-cloro-4- (metilsulfonil)fenil]amino}-6-etil-5-[(trans-4-hidroxiciclohexil)amino]pirazin-2-carboxamida (39 mg) como un solido amarillo claro.A mixture of 3,5-dichloro-6-ethylpyrazin-2-carboxamide (200 mg), 3-chloro-4-methylsulfonilaniline (374 mg) and NMP (1 ml) was stirred at 230 ° C for 1 hour using a system. of microwave reaction. From here, trans-4-aminocyclohexanol (524 mg) was added to the reaction liquid and stirred at 190 ° C for 30 minutes using a microwave reaction system. After cooling, the reaction liquid was partitioned using ethyl acetate and water, and the organic phase was washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent; chloroform: methanol = 10: 0 to 30: 1) to give a crude product. This product was heated with ethanol and washed giving a light yellow solid. To the light yellow solid, ethyl acetate was added and heated, and the insoluble materials were filtered off and the filtrate was concentrated. After concentrating the filtrate, the residue was heated and washed with ethanol giving 3 - {[3-chloro-4- (methylsulfonyl) phenyl] amino} -6-ethyl-5 - [(trans-4-hydroxycyclohexyl) amino] pyrazin-2-carboxamide (39 mg) as a light yellow solid.

Ejemplo 159Example 159

A una mezcla de 5-[(trans-4-hidroxiciclohexil)amino]-3-{[3-(metilsulfonil)fenil]amino}pirazin-2-carboxamida (Ejemplo 111) (298 mg), cloroformo (40 ml) y acetonitrilo (10 ml) se anadio N-clorosuccinimida (108 mg) y se agito a 70 °C durante 8 horas. Despues de enfriarse el lfquido de reaccion, se anadio gel de sflice, y el disolvente se separo por destilacion, seguido de purificacion por cromatograffa en columna de gel de sflice (eluyente; cloroformo:metanol = 10:0 a 10:1). El producto en bruto resultante se solidifico en cloroformo y se recogio por filtracion. El solido resultante se calento con acetato de etilo y se lavo con acetato de etilo dando 6-cloro-5-[(trans-4-hidroxiciclohexil)amino]-3-{(3- (metilsulfonil)fenil]amino}pirazin-2-carboxamida (189 mg) como un solido blanco.To a mixture of 5 - [(trans-4-hydroxycyclohexyl) amino] -3 - {[3- (methylsulfonyl) phenyl] amino} pyrazin-2-carboxamide (Example 111) (298 mg), chloroform (40 ml) and Acetonitrile (10 ml) was added N-chlorosuccinimide (108 mg) and stirred at 70 ° C for 8 hours. After the reaction liquid was cooled, silica gel was added, and the solvent was distilled off, followed by purification by silica gel column chromatography (eluent; chloroform: methanol = 10: 0 to 10: 1). The resulting crude product solidified in chloroform and was collected by filtration. The resulting solid was heated with ethyl acetate and washed with ethyl acetate to give 6-chloro-5 - [(trans-4-hydroxycyclohexyl) amino] -3 - {(3- (methylsulfonyl) phenyl] amino} pyrazin-2 -carboxamide (189 mg) as a white solid.

Ejemplo 181Example 181

A una mezcla de 5-[(trans-4-hidroxiciclohexil)amino]-3-{[3-(metilsulfonil)fenil]amino}pirazin-2-carboxamida (Ejemplo 111) (150 mg), cloroformo (40 ml) y acetonitrilo (20 ml) se anadio N-bromosuccinimida (69 mg) y se agito a temperatura ambiente durante 2 horas. Al lfquido de reaccion se anadio gel de sflice, y el disolvente se separo porTo a mixture of 5 - [(trans-4-hydroxycyclohexyl) amino] -3 - {[3- (methylsulfonyl) phenyl] amino} pyrazin-2-carboxamide (Example 111) (150 mg), chloroform (40 ml) and Acetonitrile (20 ml) N-bromosuccinimide (69 mg) was added and stirred at room temperature for 2 hours. Silica gel was added to the reaction liquid, and the solvent was removed by

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destilacion, seguido de purificacion por cromatograffa en columna de gel de s^lice (eluyente; cloroformo:metanol = 10:0 a 10:1). El producto en bruto resultante se solidifico con acetato de etilo y se lavo con acetato de etilo dando 6- bromo-5-[(trans-4-hidroxiciclohexil)amino]-3-[[3-(metilsulfonil)fenil]amino}pirazin-2-carboxamida (130 mg) como un solido amarillo claro.distillation, followed by purification by silica gel column chromatography (eluent; chloroform: methanol = 10: 0 to 10: 1). The resulting crude product was solidified with ethyl acetate and washed with ethyl acetate giving 6- bromo-5 - [(trans-4-hydroxycyclohexyl) amino] -3 - [[3- (methylsulfonyl) phenyl] amino} pyrazine -2-carboxamide (130 mg) as a light yellow solid.

Ejemplo 190Example 190

A una mezcla de 5-[(trans-4-hidroxiciclohexil)amino]-3-{[3-(metilsulfonil)fenil]amino}pirazin-2-carboxamida (Ejemplo 111) (150 mg), cloroformo (40 ml) y acetonitrilo (20 ml) se anadio N-yodosuccinimida (87 mg) y se agito a temperatura ambiente durante 2 horas. Al ffquido de reaccion se anadio gel de sflice, y el disolvente se separo por destilacion, seguido de purificacion por cromatograffa en columna de gel de sflice (eluyente; cloroformo:metanol = 10:0 a 10:1). El producto en bruto resultante solidifico con acetato de etilo y se lavo con acetato de etilo dando 5- [(trans-4-hidroxiciclohexil)amino]-6-yodo-3-{[3-(metilsulfonil)fenil]amino}pirazin-2-carboxamida (153 mg) como un solido amarillo claro.To a mixture of 5 - [(trans-4-hydroxycyclohexyl) amino] -3 - {[3- (methylsulfonyl) phenyl] amino} pyrazin-2-carboxamide (Example 111) (150 mg), chloroform (40 ml) and Acetonitrile (20 ml) was added N-iodosuccinimide (87 mg) and stirred at room temperature for 2 hours. To the reaction fluid was added silica gel, and the solvent was distilled off, followed by purification by silica gel column chromatography (eluent; chloroform: methanol = 10: 0 to 10: 1). The resulting crude product solidified with ethyl acetate and washed with ethyl acetate giving 5- [(trans-4-hydroxycyclohexyl) amino] -6-iodo-3 - {[3- (methylsulfonyl) phenyl] amino} pyrazine- 2-carboxamide (153 mg) as a light yellow solid.

Ejemplo 196Example 196

Una mezcla de 5-cloro-6-etil-3-{[3-(metilsulfonil)fenil]amino}pirazin-2-carboxamida (Ejemplo de preparacion 353) (8,8 mg), 1 -metil-piperidin-3-ilamina (8,0 mg) y NMP (0,5 ml) se calento a 190 °C durante 30 minutos usando un sistema de reaccion de microondas. Despues de enfriarse el ffquido de reaccion, la fase organica se separo por destilacion a presion reducida, y el residuo se separo y se purifico por HPLC (columna: SunFire® C18, 5 pm, 19 mm x 100 mm, disolvente: MeOH/0,1 % de HCOOH-H2O = 10/90 (0 min)-10/90 (1 min)-95/5 (9 min)-95/5 (12 min), velocidad de flujo: 25 ml/min) dando (6-etil-5-[(1-metilpiperidin-3-il)amino]-3-{[3-(metilsulfonil)fenil]amino}pirazin-2-carboxamida (2,4 mg).A mixture of 5-chloro-6-ethyl-3 - {[3- (methylsulfonyl) phenyl] amino} pyrazin-2-carboxamide (Preparation Example 353) (8.8 mg), 1-methyl-piperidin-3- Ilamine (8.0 mg) and NMP (0.5 ml) was heated at 190 ° C for 30 minutes using a microwave reaction system. After cooling the reaction fluid, the organic phase was distilled off under reduced pressure, and the residue was separated and purified by HPLC (column: SunFire® C18, 5 pm, 19 mm x 100 mm, solvent: MeOH / 0 , 1% HCOOH-H2O = 10/90 (0 min) -10/90 (1 min) -95/5 (9 min) -95/5 (12 min), flow rate: 25 ml / min) giving (6-ethyl-5 - [(1-methylpiperidin-3-yl) amino] -3 - {[3- (methylsulfonyl) phenyl] amino} pyrazin-2-carboxamide (2.4 mg).

Ejemplo 302Example 302

A una mezcla de 5-[(4-amino-4-metilciclohexil)amino]-3-{[3-(metilsulfonil)fenil]amino}-6-propilpirazin-2-carboxamida (Ejemplo 301) (89 mg) y diclorometano (5 ml) se anadieron formalina (0,30 ml) y triacetoxiborohidruro de sodio (82 mg) y se agito a temperatura ambiente durante 1,5 horas. Despues de diluir el ffquido de reaccion con cloroformo, se lavo con hidrogenocarbonato de sodio acuoso saturado y se seco sobre sulfato de magnesio anhidro. Despues de separar el agente secante por filtracion, se anadio gel de sflice, y el disolvente se separo por destilacion, seguido de purificacion del residuo por cromatograffa en columna de gel de sffice (eluyente; cloroformo:metanol:amoniaco acuoso saturado = 10:0:0 a 10:1:0,1). El residuo resultante se lavo con acetato de etilo dando 5-{[4-(dimetilamino)-4- metilciclohexil]amino}-3-{[3-(metilsulfonil)fenil]amino}-6-propilpirazin-2-carboxamida (31 mg) como un solido amarillo claro.To a mixture of 5 - [(4-amino-4-methylcyclohexyl) amino] -3 - {[3- (methylsulfonyl) phenyl] amino} -6-propylpyrazin-2-carboxamide (Example 301) (89 mg) and dichloromethane (5 ml) formalin (0.30 ml) and sodium triacetoxyborohydride (82 mg) were added and stirred at room temperature for 1.5 hours. After diluting the reaction fluid with chloroform, it was washed with saturated aqueous sodium hydrogen carbonate and dried over anhydrous magnesium sulfate. After separating the drying agent by filtration, silica gel was added, and the solvent was distilled off, followed by purification of the residue by silica gel column chromatography (eluent; chloroform: methanol: saturated aqueous ammonia = 10: 0 : 0 to 10: 1: 0,1). The resulting residue was washed with ethyl acetate to give 5 - {[4- (dimethylamino) -4-methylcyclohexyl] amino} -3 - {[3- (methylsulfonyl) phenyl] amino} -6-propylpyrazin-2-carboxamide (31 mg) as a light yellow solid.

Ejemplo 309Example 309

A una mezcla de 6-etil-5-[(cis-4-hidroxi-4-metilciclohexil)amino]-3-[(4-metil-3-nitrofenil)amino]pirazin-2-carboxamida (Ejemplo 308) (242 mg) y metanol (10 ml) se anadio 5% de paladio sobre carbono (25 mg) y se agito bajo una atmosfera de hidrogeno a temperatura ambiente durante 4 horas. Despues de la filtracion del ffquido de reaccion, el filtrado se concentro a presion reducida dando 3-[(3-amino-4-metilfenil)amino]-6-etil-5-[(cis-4-hidroxi-4- metilciclohexil)amino]pirazin-2-carboxamida (162 mg) como un solido verde.To a mixture of 6-ethyl-5 - [(cis-4-hydroxy-4-methylcyclohexyl) amino] -3 - [(4-methyl-3-nitrophenyl) amino] pyrazin-2-carboxamide (Example 308) (242) mg) and methanol (10 ml) 5% palladium on carbon (25 mg) was added and stirred under a hydrogen atmosphere at room temperature for 4 hours. After filtration of the reaction fluid, the filtrate was concentrated under reduced pressure to give 3 - [(3-amino-4-methylphenyl) amino] -6-ethyl-5 - [(cis-4-hydroxy-4-methylcyclohexyl)) amino] pyrazin-2-carboxamide (162 mg) as a green solid.

Ejemplo 310Example 310

A una mezcla de 3-[(3-amino-4-metilfenil)amino]-6-etil-5-[(cis-4-hidroxi-4-metilciclohexil)amino]pirazin-2-carboxamida (Ejemplo 309) (150 mg), THF (2 ml) y DMF (2 ml) se anadieron N,N-diisopropiletilamina (49 mg) y cloruro del acido acrffico (34 mg) bajo enfriamiento con hielo y se agito durante 30 minutos. El ffquido de reaccion se vertio en agua y se extrajo con acetato de etilo. La fase organica se lavo con agua y cloruro sodico acuoso saturado secuencialmente y a continuacion se seco sobre sulfato de sodio anhidro, y el disolvente se separo por destilacion a presion reducida. El residuo se purifico por cromatograffa en columna de gel de sffice (eluyente; cloroformo:metanol) dando 3-{[3- (acriloilamino)-4-metilfenil]amino}-6-etil-5-[(cis-4-hidroxi-4-metilciclohexil)amino]pirazin-2-carboxamida (48 mg) como un polvo amarillo claro.To a mixture of 3 - [(3-amino-4-methylphenyl) amino] -6-ethyl-5 - [(cis-4-hydroxy-4-methylcyclohexyl) amino] pyrazin-2-carboxamide (Example 309) (150 mg), THF (2 ml) and DMF (2 ml) were added N, N-diisopropylethylamine (49 mg) and acrylic acid chloride (34 mg) under ice cooling and stirred for 30 minutes. The reaction fluid was poured into water and extracted with ethyl acetate. The organic phase was washed with water and saturated aqueous sodium chloride sequentially and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent; chloroform: methanol) to give 3 - {[3- (acryloylamino) -4-methylphenyl] amino} -6-ethyl-5 - [(cis-4-hydroxy -4-methylcyclohexyl) amino] pyrazin-2-carboxamide (48 mg) as a light yellow powder.

Ejemplo 343Example 343

A una mezcla de 5-[(trans-4-hidroxiciclohexil)amino]-6-isopropenil-3-{[4-(4-metilpiperazin-1-il)fenil]amino}pirazin-2- carboxamida (Ejemplo 342) (205 mg), etanol (20 ml) y THF (10 ml) se anadio 10 % de paladio sobre carbono (100 mg) bajo una atmosfera de hidrogeno y se agito a temperatura ambiente durante 18 horas. Despues de separar el catalizador por filtracion, el disolvente se separo por destilacion, y el residuo se purifico por cromatograffa en columna de gel de sffice basica (eluyente: cloroformo). El solido amarillo resultante se lavo con acetato de etilo dando 5-[(trans-4-hidroxiciclohexil)amino]-6-isopropil-3-{[4-(4-metilpiperazin-1-il)fenil]amino}pirazin-2-carboxamida (136 mg) como un solido amarillo.To a mixture of 5 - [(trans-4-hydroxycyclohexyl) amino] -6-isopropenyl-3 - {[4- (4-methylpiperazin-1-yl) phenyl] amino} pyrazine-2-carboxamide (Example 342) ( 205 mg), ethanol (20 ml) and THF (10 ml) 10% palladium on carbon (100 mg) was added under an atmosphere of hydrogen and stirred at room temperature for 18 hours. After separating the catalyst by filtration, the solvent was distilled off, and the residue was purified by basic silica gel column chromatography (eluent: chloroform). The resulting yellow solid was washed with ethyl acetate giving 5 - [(trans-4-hydroxycyclohexyl) amino] -6-isopropyl-3 - {[4- (4-methylpiperazin-1-yl) phenyl] amino} pyrazin-2 -carboxamide (136 mg) as a yellow solid.

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Ejemplo 381Example 381

A una mezcla de 4-[4-({3-carbamoil-5-etil-6-[(trans-4-hidroxiciclohexil)amino]pirazin-2-il}amino)-2- metoxifenil]piperidin-1-carboxilato de terc-butilo (Ejemplo 382) (270 mg) y acetato de etilo (10 ml) se anadio cloruro de hidrogeno 4 M en acetato de etilo (4 ml) bajo enfriamiento con hielo y se agito a temperatura ambiente durante 1 hora. El ffquido de reaccion se concentro a presion reducida, y al residuo se anadieron hidrogenocarbonato de sodio acuoso saturado y cloroformo. El solido precipitado se recogio por filtracion y se seco dando 6-etil-5-[(trans-4- hidroxiciclohexil)amino]-3-[(3-metoxi-4-piperidin-4-ilfenil)amino]pirazin-2-carboxamida (85 mg) como un solido amarillo claro.To a mixture of 4- [4 - ({3-carbamoyl-5-ethyl-6 - [(trans-4-hydroxycyclohexyl) amino] pyrazin-2-yl} amino) -2-methoxyphenyl] piperidine-1-carboxylate of tert-butyl (Example 382) (270 mg) and ethyl acetate (10 ml) 4M hydrogen chloride in ethyl acetate (4 ml) was added under ice cooling and stirred at room temperature for 1 hour. The reaction fluid was concentrated under reduced pressure, and saturated aqueous sodium hydrogen carbonate and chloroform were added to the residue. The precipitated solid was collected by filtration and dried to give 6-ethyl-5 - [(trans-4- hydroxycyclohexyl) amino] -3 - [(3-methoxy-4-piperidin-4-ylphenyl) amino] pyrazine-2- carboxamide (85 mg) as a light yellow solid.

Ejemplo 405Example 405

A una mezcla de 6-etil-5-[(trans-4-hidroxiciclohexil)amino]-3-[(4-piperidin-4-ilfenil)amino]pirazin-2-carboxamida (Ejemplo 358) (43 mg) y dicloroetano (1 ml) se anadieron piridina (0,01 ml) y anhffdrido acetico (0,01 ml) bajo enfriamiento con hielo y se agito a temperatura ambiente durante 20 minutos. Despues de la adicion de hidrogenocarbonato de sodio acuoso saturado, el ffquido de reaccion se repartio usando cloroformo e hidrogenocarbonato de sodio acuoso saturado. Despues de secar sobre sulfato de sodio anhidro, la fase organica se concentro, y el residuo resultante solidifico con acetato de etilo-hexano dando 3-{[4-(1-acetilpiperidin-4- il)fenil]amino}-6-etil-5-[(trans-4-hidroxiciclohexil)amino]pirazin-2-carboxamida (26 mg) como un solido blanco.To a mixture of 6-ethyl-5 - [(trans-4-hydroxycyclohexyl) amino] -3 - [(4-piperidin-4-ylphenyl) amino] pyrazin-2-carboxamide (Example 358) (43 mg) and dichloroethane (1 ml) pyridine (0.01 ml) and acetic anhydride (0.01 ml) were added under ice cooling and stirred at room temperature for 20 minutes. After the addition of saturated aqueous sodium hydrogen carbonate, the reaction fluid was partitioned using chloroform and saturated aqueous sodium hydrogen carbonate. After drying over anhydrous sodium sulfate, the organic phase was concentrated, and the resulting residue solidified with ethyl acetate-hexane giving 3 - {[4- (1-acetylpiperidin-4- yl) phenyl] amino} -6-ethyl -5 - [(trans-4-hydroxycyclohexyl) amino] pyrazin-2-carboxamide (26 mg) as a white solid.

Ejemplo 436Example 436

A una mezcla de 4-[(5-carbamoil-3-etil-6-{[4-(4-metilpiperazin-1-il)-3-(trifluorometil)fenil]amino}pirazin-2- il)amino]ciclohexanocarboxilato de metilo (Ejemplo 435) (126 mg), THF (2 ml) y metanol (2 ml) se anadio 10 % de hidroxido sodico acuoso (1 ml) y se calento a reflujo durante 2 horas. Al ffquido de reaccion se anadio 10 % de acido clorhfdrico para dar un pH de aproximadamente 7, y el solido resultante se recogio por filtracion. Este solido se purifico por cromatograffa en columna de gel de sffice (eluyente; cloroformo:metanol) dando acido 4-[(5-carbamoil-3- etil-6-{[4-(4-metilpiperazin-1-il)-3-(trifluorometil)fenil]amino}pirazin-2-il)amino]ciclohexanocarboxffico (Ejemplo 436) (47 mg), que fue un producto de baja polaridad, como un polvo amarillo-blanco claro y acido 4-[(5-carbamoil-3-etil-6- {[4-(4-metilpiperazin-1-il)-3-(trifluorometil)fenil]amino}pirazin-2-il)amino]ciclohexanocarboxffico (Ejemplo 437) (59 mg), que fue un producto de alta polaridad, como un polvo amarillo claro.To a mixture of 4 - [(5-carbamoyl-3-ethyl-6 - {[4- (4-methylpiperazin-1-yl) -3- (trifluoromethyl) phenyl] amino} pyrazin-2-yl) amino] cyclohexanecarboxylate of methyl (Example 435) (126 mg), THF (2 ml) and methanol (2 ml) 10% aqueous sodium hydroxide (1 ml) was added and heated under reflux for 2 hours. To the reaction fluid was added 10% hydrochloric acid to give a pH of approximately 7, and the resulting solid was collected by filtration. This solid was purified by sffice gel column chromatography (eluent; chloroform: methanol) to give acid 4 - [(5-carbamoyl-3- ethyl-6 - {[4- (4-methylpiperazin-1-yl) -3 - (trifluoromethyl) phenyl] amino} pyrazin-2-yl) amino] cyclohexanecarboxylic acid (Example 436) (47 mg), which was a low polarity product, such as a light yellow-white powder and 4 - [(5-carbamoyl acid) -3-ethyl-6- {[4- (4-methylpiperazin-1-yl) -3- (trifluoromethyl) phenyl] amino} pyrazin-2-yl) amino] cyclohexanecarboxylic acid (Example 437) (59 mg), which was a high polarity product, such as a light yellow powder.

Ejemplo 438Example 438

A una mezcla de acido 4-[(5-carbamoil-3-etil-6-{[4-(4-metilpiperazin-1-il)-3-(trifluorometil)fenil]amino}pirazin-2- il)amino] ciclohexanocarboxffico (Ejemplo 436) (62 mg), o-anisidina (42 mg) y DMF (2 ml) se anadieron 1-hidroxi-1H- benzotriazol monohidratado (46 mg) y clorhidrato de 1-etil-3-(3-dimetilaminopropil)carbodiimida (65 mg) y se agito a temperatura ambiente durante 7 horas. El ffquido de reaccion se vertio en hidrogenocarbonato de sodio acuoso saturado y se extrajo con acetato de etilo. La fase organica se lavo con agua y cloruro sodico acuoso saturado secuencialmente y a continuacion se seco sobre sulfato de sodio anhidro, y el disolvente se separo por destilacion a presion reducida. El residuo se purifico por cromatograffa en columna de gel de sffice (eluyente; cloroformo:metanol) dando 6-etil-5-({4-[(2-metoxi-fenil)carbamoil]ciclohexil}amino)-3-{[4-(4-metilpiperazin-1-il)-3-To a mixture of 4 - [(5-carbamoyl-3-ethyl-6 - {[4- (4-methylpiperazin-1-yl) -3- (trifluoromethyl) phenyl] amino} pyrazin-2-yl) amino] acid] cyclohexanecarboxyffic (Example 436) (62 mg), o-anisidine (42 mg) and DMF (2 ml) 1-hydroxy-1H-benzotriazole monohydrate (46 mg) and 1-ethyl-3- hydrochloride (3-dimethylaminopropyl) ) carbodiimide (65 mg) and stirred at room temperature for 7 hours. The reaction fluid was poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic phase was washed with water and saturated aqueous sodium chloride sequentially and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent; chloroform: methanol) to give 6-ethyl-5 - ({4 - [(2-methoxy-phenyl) carbamoyl] cyclohexyl} amino) -3 - {[4 - (4-methylpiperazin-1-yl) -3-

(trifluorometil)fenil]amino}pirazin-2-carboxamida (33 mg) como un polvo amarillo.(trifluoromethyl) phenyl] amino} pyrazin-2-carboxamide (33 mg) as a yellow powder.

Ejemplo 495Example 495

Una mezcla de 6-cloro-3-{[3-(1,4-dioxa-8-azaespiro[4.5]deca-8-il)-4-metoxifenil]amino}-5-[(trans-4- hidroxiciclohexil)amino]pirazin-2-carboxamida (Ejemplo 482) (0,80 g), acido acetico (4 ml) y agua (4 ml) se agito a 80 °C durante 3 horas. Al ffquido de reaccion se anadio acido clorhfdrico concentrado (1 ml) y se agito a 80 °C durante 2 horas. El ffquido de reaccion se enfrio y se concentro a presion reducida, y entonces se anadio cloroformo, seguido de lavado con hidrogenocarbonato de sodio acuoso saturado. Despues de secar la fase organica sobre sulfato de magnesio anhidro, el disolvente se separo por destilacion, seguido de purificacion por cromatograffa en columna de gel de sffice (eluyente; cloroformo:metanol = 10:1 a 30:1) dando 6-cloro-5-[(trans-4-A mixture of 6-chloro-3 - {[3- (1,4-dioxa-8-azaspiro [4.5] deca-8-yl) -4-methoxyphenyl] amino} -5 - [(trans-4- hydroxycyclohexyl) amino] pyrazin-2-carboxamide (Example 482) (0.80 g), acetic acid (4 ml) and water (4 ml) was stirred at 80 ° C for 3 hours. To the reaction fluid, concentrated hydrochloric acid (1 ml) was added and stirred at 80 ° C for 2 hours. The reaction liquid was cooled and concentrated under reduced pressure, and then chloroform was added, followed by washing with saturated aqueous sodium hydrogen carbonate. After drying the organic phase over anhydrous magnesium sulfate, the solvent was distilled off, followed by purification by silica gel column chromatography (eluent; chloroform: methanol = 10: 1 to 30: 1) giving 6-chloro- 5 - [(trans-4-

hidroxiciclohexil)amino]-3-{[4-metoxi-3-(4-oxopiperidin-1-il)fenil]amino}pirazin-2-carboxamida (0,74 g) como un amorfo amarillo.hydroxycyclohexyl) amino] -3 - {[4-methoxy-3- (4-oxopiperidin-1-yl) phenyl] amino} pyrazin-2-carboxamide (0.74 g) as a yellow amorphous.

Ejemplo 499Example 499

A una mezcla de 6-cloro-5-[(trans-4-hidroxiciclohexil)amino]-3-{[4-metoxi-3-(4-oxopiperidin-1-il)fenil]amino}pirazin-2- carboxamida (Ejemplo 495) (0,346 mg), N-metilpiperazina (0,12 ml) y 1,2-dicloroetano (10 ml) se anadio triacetoxiborohidruro de sodio (225 mg) y se agito a temperatura ambiente durante 5 horas. Despues de la adicion de hidrogenocarbonato de sodio acuoso saturado, el ffquido de reaccion se extrajo con cloroformo, y la fase organica se lavo con cloruro sodico acuoso saturado. Despues de secar sobre sulfato de sodio anhidro, el disolvente se separo por destilacion a presion reducida, y el residuo se purifico por cromatograffa en columna de gel de sffice (eluyente; cloroformo:metanol:amoniaco acuoso saturado = 100:0:0 a 20:1:0,1) dando un producto en bruto. El producto en bruto solidifico con acetato de etilo-eter diisopropffico y a continuacion se lavo con acetato de etiloTo a mixture of 6-chloro-5 - [(trans-4-hydroxycyclohexyl) amino] -3 - {[4-methoxy-3- (4-oxopiperidin-1-yl) phenyl] amino} pyrazine-2-carboxamide ( Example 495) (0.346 mg), N-methylpiperazine (0.12 ml) and 1,2-dichloroethane (10 ml) sodium triacetoxyborohydride (225 mg) was added and stirred at room temperature for 5 hours. After the addition of saturated aqueous sodium hydrogen carbonate, the reaction fluid was extracted with chloroform, and the organic phase was washed with saturated aqueous sodium chloride. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by sffice gel column chromatography (eluent; chloroform: methanol: saturated aqueous ammonia = 100: 0: 0 to 20 : 1: 0,1) giving a raw product. The crude product solidified with ethyl acetate-diisoprophic ether and then washed with ethyl acetate

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dando 6-cloro-5-[(trans-4-hidroxiciclohexil)amino]-3-({4-metoxi-3-[4-(4-metilpiperazin-1-il)piperidin-1-giving 6-chloro-5 - [(trans-4-hydroxycyclohexyl) amino] -3 - ({4-methoxy-3- [4- (4-methylpiperazin-1-yl) piperidin-1-

il]fenil}amino)pirazin-2-carboxamida (39 mg) como un solido amarillo claro.il] phenyl} amino) pyrazin-2-carboxamide (39 mg) as a light yellow solid.

Ejemplo 508Example 508

Una mezcla de 6-bromo-5-[(trans-4-hidroxiciclohexil)amino]-3-[[3-(metilsulfonil)fenil]amino}pirazin-2-carboxamida (Ejemplo 181) (50 mg), acido ciclopropilboronico (18 mg), tetraquistrifenilfosfina-paladio (24 mg), carbonato de potasio (71 mg), dioxano (2,5 ml) y agua (0,5 ml) se agito a 115 °C durante la noche. Despues de enfriarse, el lfquido de reaccion se repartio usando cloroformo, hidrogenocarbonato de sodio acuoso saturado y cloruro sodico acuoso saturado. Despues de secar, la fase organica se concentro, y el residuo resultante se purifico por cromatograffa en columna de gel de sflice (eluyente; cloroformo:metanol:amoniaco acuoso saturado = 100:0:0 a 10:1:0,1). El residuo resultante solidifico con acetato de etilo-hexano dando 6-ciclopropil-5-[(trans-4-hidroxiciclohexil)amino]-3-{[3- (metilsulfonil)fenil]amino}pirazin-2-carboxamida (10 mg) como un solido amarillo.A mixture of 6-bromo-5 - [(trans-4-hydroxycyclohexyl) amino] -3 - [[3- (methylsulfonyl) phenyl] amino} pyrazin-2-carboxamide (Example 181) (50 mg), cyclopropylboronic acid ( 18 mg), tetraquistriphenylphosphine palladium (24 mg), potassium carbonate (71 mg), dioxane (2.5 ml) and water (0.5 ml) was stirred at 115 ° C overnight. After cooling, the reaction liquid was partitioned using chloroform, saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride. After drying, the organic phase was concentrated, and the resulting residue was purified by silica gel column chromatography (eluent; chloroform: methanol: saturated aqueous ammonia = 100: 0: 0 to 10: 1: 0.1). The resulting residue solidified with ethyl acetate-hexane giving 6-cyclopropyl-5 - [(trans-4-hydroxycyclohexyl) amino] -3 - {[3- (methylsulfonyl) phenyl] amino} pyrazine-2-carboxamide (10 mg) Like a yellow solid

Ejemplo 534Example 534

A una mezcla de 5-[(1-bencilpiperidin-4-il)amino]-6-etil-3-({3-metil-4-[4(4-metilpiperazin-1-il)piperidin-1- il]fenil}amino)pirazin-2-carboxamida (Ejemplo 507) (1,31 g), etanol (26 ml) y acido acetico (13 ml) se anadio hidroxido de paladio (0,65 g) y se agito bajo una atmosfera de hidrogeno a temperatura ambiente durante 3 dfas. Despues de separar el catalizador por filtracion, el disolvente se concentro y se repartio usando cloroformo e hidrogenocarbonato de sodio acuoso saturado. La fase organica se concentro dando 6-etil-3-({3-metil-4-[4-(4- metilpiperazin-1-il)piperidin-1-il]fenil}amino)-5-(piperidin-4-ilamino)pirazin-2-carboxamida (0,73 g) como un solido amarillo claro.To a mixture of 5 - [(1-benzylpiperidin-4-yl) amino] -6-ethyl-3 - ({3-methyl-4- [4 (4-methylpiperazin-1-yl) piperidin-1- yl] phenyl} amino) pyrazin-2-carboxamide (Example 507) (1.31 g), ethanol (26 ml) and acetic acid (13 ml) palladium hydroxide (0.65 g) was added and stirred under an atmosphere of hydrogen at room temperature for 3 days. After separating the catalyst by filtration, the solvent was concentrated and partitioned using saturated aqueous sodium chloroform and hydrogen carbonate. The organic phase was concentrated to give 6-ethyl-3 - ({3-methyl-4- [4- (4- methylpiperazin-1-yl) piperidin-1-yl] phenyl} amino) -5- (piperidin-4- ylamino) pyrazin-2-carboxamide (0.73 g) as a light yellow solid.

Las Tablas 85 a 164 muestran las estructuras qmmicas de los compuestos preparados en los ejemplos anteriores, y las estructuras qmmicas de los compuestos de ejemplos preparados de la misma forma que se muestra en los ejemplos anteriores usando materiales de partida correspondientes. Las Tablas 165 a 183 muestran los procesos de preparacion y datos ffsicos y qmmicos de estos compuestos de ejemplos.Tables 85 to 164 show the chemical structures of the compounds prepared in the previous examples, and the chemical structures of the compounds of examples prepared in the same manner as shown in the previous examples using corresponding starting materials. Tables 165 to 183 show the processes of preparation and physical and chemical data of these example compounds.

[Tabla 7][Table 7]

Rex  Rex
Estructura Rex Estructura  Structure Rex Structure

1  one
NHa q Me ^ 8 Yi fYfMe YnyYANO;> 0 ‘  NHa q Me ^ 8 Yi fYfMe YnyYANO;> 0 ‘

2  2
^H2 Q| YyS Me H 9 rjY° NH xYj'^'N^SMe Me ^  ^ H2 Q | YyS Me H 9 rjY ° NH xYj '^' N ^ SMe Me ^

3  3
EL.N /=\ " ^4 }—Me nh2 10 Ca^0 NH A° yS Y^lYlYsMe Me H  EL.N / = \ "^ 4} —Me nh2 10 Ca ^ 0 NH A ° yS Y ^ lYlYsMe Me H

4  4
TQ- no2 11 H iPr>AMe NH>  TQ- no2 11 H iPr> AMe NH>

5  5
Et2N^O NH3 To=\ S n y> Me H 12 H iPr-N /=\ NOj  Et2N ^ O NH3 To = \ S n y> Me H 12 H iPr-N / = \ NOj

Rex  Rex
Estructura Rex Estructura  Structure Rex Structure

6  6
EyV° NHaa fXri T'lT'A^e Me H 13 H k,u 1 left O Ji T M SMe Me ^  EyV ° NHaa fXri T'lT'A ^ e Me H 13 H k, u 1 left O Ji T M SMe Me ^

7  7
Ln^XXNH2 0 14 H Nv^O i. j M \p/ r yH29] IX A A y^N'^Nr'SMe Me H  Ln ^ XXNH2 0 14 H Nv ^ O i. j M \ p / r yH29] IX A A and ^ N '^ Nr'SMe Me H

[Tabla 81[Table 81

RexRex

EstructuraStructure

RexRex

EstructuraStructure

15fifteen

imagen27image27

2222

imagen28image28

1616

232. 3

imagen29image29

1717

imagen30image30

2424

imagen31image31

1818

2525

imagen32image32

1919

2626

imagen33image33

20twenty

imagen34image34

2727

imagen35image35

21twenty-one

imagen36image36

2828

imagen37image37

[Tabla 91[Table 91

Rex  Rex
Estructura Rex Estructura  Structure Rex Structure

29  29
H ft /=\ NH? 36 VTVnh, iPr-N Y ‘ H Cl7  H ft / = \ NH? 36 VTVnh, iPr-N Y ‘H Cl7

30  30
F’r. IjJH oAo NH20 Y n=L JL iTTf Ms H 37 Vf>N02 iPr-W W H Cl  F’r. IjJH oAo NH20 Y n = L JL iTTf Ms H 37 Vf> N02 iPr-W W H Cl

31  31
iPrN hJH 0=s=0 NH2n ffi° l! N | J Jl f Y^N N SMe Me H 38 0 S)IH2o iPK A ^\0=k 1 " n xr Cf^^NAAsMe H  iPrN hJH 0 = s = 0 NH2n ffi ° l! N | J Jl f Y ^ N N SMe Me H 38 0 S) IH2o iPK A ^ \ 0 = k 1 "n xr Cf ^^ NAAsMe H

32  32
Me"NH 0=^0Y0 ClTT YNY SMe Me ^ 39 9 Cl iP^ A. H K JUU Cl^'v/ N N SMe H  Me "NH 0 = ^ 0Y0 ClTT YNY SMe Me ^ 39 9 Cl iP ^ A. H K JUU Cl ^ 'v / N N SMe H

33  33
Mes NH O^SO ^H2CI 1 o4 I n n Y^ lAsMe L H 40 /AsiJ|_AA_-nh2 x— 6 MeO  Month NH O ^ SO ^ H2CI 1 o4 I n n Y ^ lAsMe L H 40 / AsiJ | _AA_-nh2 x— 6 MeO

34  3. 4
0 j^2 q cV'^^'N'^N^SMe H 41 ( W-|>—/ V-NQ, v—'7 6 W " Med  0 j ^ 2 q cV '^^' N '^ N ^ SMe H 41 (W- |> - / V-NQ, v — '7 6 W "Med

35  35
Q nheci T^° ci'^^N'^'N^SMe 42 Gy yy MeO'^^N'^'A'SMe H  Q nheci T ^ ° ci '^^ N' ^ 'N ^ SMe 42 Gy yy MeO' ^^ N '^' A'SMe H

[Tabla 101[Table 101

Rex  Rex
Estructura Rex Estructura  Structure Rex Structure

43  43
A/ JY n'Yo FN 0 L II II T MaO'^^A'Ar'SMe H 50 A Cl F. ......Oh... JL h YX jpr.N.._YY^N>-fAsiVle 0 H  A / JY n'Yo FN 0 L II II T MaO '^^ A'Ar'SMe H 50 A Cl F. ...... Oh ... JL h YX jpr.N .._ YY ^ N> - fAsiVle 0 H

44  44
ft MeO 51 O ■ - ' ^ V '-- "' NH:, o  ft MeO 51 O ■ - '^ V' - "'NH :, or

45  Four. Five
^fP"^ MeO7 52 A O AN^YA'55^N^N^SMe O H  ^ fP "^ MeO7 52 A O AN ^ YA'55 ^ N ^ N ^ SMe O H

Rex  Rex
Estructura Rex Estructura  Structure Rex Structure

46  46
O nh dr rlYf N'SMe H 53 fa Cl ^ fy^o=Yam o H  O nh dr rlYf N'SMe H 53 fa Cl ^ fy ^ o = Yam or H

47  47
n NH, Ft N P 2 01 o' Y\jS A .A. A H 54 fko 9"f f^'N^N^SMe O H  n NH, Ft N P 2 01 or 'Y \ jS A .A. A H 54 fko 9 "f f ^ 'N ^ N ^ SMe O H

48  48
H FY"1 0 55 Ql n Frf V? 6 H  H FY "1 0 55 Ql n Frf V? 6 H

49  49
h YYYt iP^-Y^'^N'^N^'SMe 6 H 56 Fr> Et A  h YYYt iP ^ -Y ^ '^ N' ^ N ^ 'SMe 6 H 56 Fr> Et A

[Tabla 111[Table 111

RexRex

EstructuraStructure

RexRex

EstructuraStructure

5757

imagen38image38

6464

imagen39image39

5858

imagen40image40

6565

imagen41image41

5959

imagen42image42

6666

6060

imagen43image43

6767

imagen44image44

6161

imagen45image45

6868

imagen46image46

6262

6969

imagen47image47

Rex  Rex
Estructura Rex Estructura  Structure Rex Structure

63  63
fl /=v P nh2 70 9 gp H  fl / = v P nh2 70 9 gp H

[Tabla 121[Table 121

Rex  Rex
Estructura Rex Estructura  Structure Rex Structure

71  71
° /—. X~f V-nh, Me-N >=‘ r' Me 78 nMeYi O  ° / -. X ~ f V-nh, Me-N> = ‘r 'Me 78 nMeYi O

72  72
o ,__k y ^V-no Me~N V=/ HMef 79 nMe"Ti 6  o, __ k and ^ V-no Me ~ N V = / HMef 79 nMe "Ti 6

73  73
9 mh2o Me 80 nh2 q k/NY^'^'N'^'N^SMe O H  9 mh2o Me 80 nh2 q k / NY ^ '^' N '^' N ^ SMe O H

74  74
h L jl 1 I Me/VAN N^Slfe H 81 NH,C| i n  h L jl 1 I Me / VAN N ^ Slfe H 81 NH, C | i n

75  75
0 82 H ! |j  0 82 H! | j

76  76
O NHa0 '"MeO'^^N^'N^SMe H 83 hVtVr o H  O NHa0 '"MeO' ^^ N ^ 'N ^ SMe H 83 hVtVr or H

77  77
O NK, Q| H 84 ^ C! hYm Me"N^/J^/^N'A'N^SMe 6 H  O NK, Q | H 84 ^ C! hYm Me "N ^ / J ^ / ^ N'A'N ^ SMe 6 H

5 ___________________________________________[Tabla 1315 ___________________________________________ [Table 131

Rex  Rex
Estructura Rex Estructura  Structure Rex Structure

85  85
FaC 92 Me"N-L. u n -'r^ Yi H °i 1 MeO'^^'NO,  FaC 92 Me "N-L. U n -'r ^ Yi H ° i 1 MeO '^^' NO,

86  86
0 NH, o “VrtV-r F' 3 H 93 ,1P T’9 Me' Yv^O<Xmu o y f, j yH MeO'' ::;%/L>J'A'N^SMe H  0 NH, or “VrtV-r F '3 H 93, 1P T’9 Me' Yv ^ O <Xmu o y f, j yH MeO '' ::;% / L> J'A'N ^ SMe H

87  87
0 JH , Vrfrx 3 H 94 °XX XX MeO N i'u’SMe n  0 JH, Vrfrx 3 H 94 ° XX XX MeO N i'u’SMe n

88  88
h Fn Me"NY^ NH2 O 95 V-/~V-NHa Me—N W n MeO  h Fn Me "NY ^ NH2 O 95 V- / ~ V-NHa Me — N W n MeO

Rex  Rex
Estructura Rex Estructura  Structure Rex Structure

89  89
nsh20 s= A h Y) rr m A >!. Me'Y^iArSMe o H 96 Y Vno2 Me-N >=/ H < n MeO  nsh20 s = A h Y) rr m A> !. Me'Y ^ iArSMe or H 96 Y Vno2 Me-N> = / H <n MeO

90  90
NH2ci H YY If 1 Me"NY'"' ' jjj" Y"'SMe 97 Q f*,o y%h H Jl i MeOyV'^N N^SMe H  NH2ci H YY If 1 Me "NY '"' 'jjj "Y"' SMe 97 Q f *, o y% h H Jl i MeOyV '^ N N ^ SMe H

91  91
0 H6r\ MeO^^ NHa 98 Q ^ ci Me^Jl aO=\ I h j3Tix MeO' ^ N" N SMe H  0 H6r \ MeO ^^ NHa 98 Q ^ ci Me ^ Jl aO = \ I h j3Tix MeO '^ N "N SMe H

[Tabla 141[Table 141

Rex  Rex
Estructura Rex Estructura  Structure Rex Structure

99  99
? GXX ^f3C 106 NHao hV|V> Me^Y^^^SMe o H  ? GXX ^ f3C 106 NHao hV | V> Me ^ Y ^^^ SMe or H

100  100
3 nXY v H 107 nh,ci h ''Y |° y Y  3 nXY v H 107 nh, ci h '' Y | ° y Y

101  101
0 NH2 Cl rryT^ 3 H 108 NHS Ck^^O^VN^Et H T 1 T T fi H  0 NH2 Cl rryT ^ 3 H 108 NHS Ck ^^ O ^ VN ^ Et H T 1 T T fi H

102  102
---- ZI “VA* M O rn 109 HN"Me NH2 °'lsY0 n 1 SYnXna.C| OMe H  ---- ZI “VA * M O rn 109 HN" Me NH2 ° 'lsY0 n 1 SYnXna.C | OMe H

103  103
9 NHa XnY^0=ynyb OpYvX 110 Me °>-<G“NH2 Me - N H  9 NHa XnY ^ 0 = ynyb OpYvX 110 Me °> - <G “NH2 Me - N H

104  104
0 NHa Me^rY0 ifNTEt H 111 Me y-4 v-no Me-N '=/ H  0 NHa Me ^ rY0 ifNTEt H 111 Me y-4 v-no Me-N '= / H

105  105
nh2 O H 112 .Me HN NH2 °*Vf’YYa YY^Yci Me H  nh2 O H 112 .Me HN NH2 ° * Vf’YYa YY ^ Yci Me H

Rex  Rex
Estructura Rex Estructura  Structure Rex Structure

113  113
o nh2 MA[Yt;^0=1,N^E1 H 11 IT F,C'''^A'A' XI J rl 120 H Yl \f Ji. Tl W2 O Cl  or nh2 MA [Yt; ^ 0 = 1, N ^ E1 H 11 IT F, C '' '^ A'A' XI J rl 120 H Yl \ f Ji. Tl W2 O Cl

114  114
H fl Me y Y^NH2 0 Me 121 M6'Vt N°a O Cl  H fl Me and Y ^ NH2 0 Me 121 M6'Vt N ° a O Cl

115  115
nh2 H [ I | T Me"NY 'Y™^|\fxi O Me H 122 nh2 H [ 1 II I Me"N'Y Y'^'U^'01 O Cl H  nh2 H [I | T Me "NY 'Y ™ ^ | \ fxi O Me H 122 nh2 H [1 II I Me" N'Y Y' ^ 'U ^ '01 O Cl H

116  116
9 ^ ^ifr" H 123 fjSH2n v^XXjf1 ^ N N SMe H  9 ^ ^ ifr "H 123 fjSH2n v ^ XXjf1 ^ N N SMe H

117  117
NHa ^OA^NyEt (^SrA'N'A'N'^CI J-* ^ 124 NH2 Cl QXXa ^ NNSMe H  NHa ^ OA ^ NyEt (^ SrA'N'A'N '^ CI J- * ^ 124 NH2 Cl QXXa ^ NNSMe H

118  118
H Me—N /=\ nh2 125 NH, i V-°Y,N.Xt W1 J Y X"'YYn,'XI H  H Me — N / = \ nh2 125 NH, i V- ° Y, N. Xt W1 J Y X "'YYn,' XI H

119  119
H Me'V® V. xA Jv T N^N' Cl p H 126 H ,o j*2 Me^oA 0 MeO^^N^hTTI H  H Me'V® V. xA Jv T N ^ N 'Cl p H 126 H, or j * 2 Me ^ oA 0 MeO ^^ N ^ hTTI H

[Tabla 161[Table 161

RexRex

EstructuraStructure

RexRex

EstructuraStructure

127127

imagen48image48

134134

imagen49image49

128128

imagen50image50

135135

129129

imagen51image51

136136

imagen52image52

130130

imagen53image53

137137

imagen54image54

131131

imagen55image55

138138

imagen56image56

RexRex

EstructuraStructure

RexRex

EstructuraStructure

132132

imagen57image57

139139

imagen58image58

133133

140140

imagen59image59

[Tabla 17][Table 17]

RexRex

EstructuraStructure

RexRex

EstructuraStructure

141141

imagen60image60

148148

imagen61image61

142142

imagen62image62

149149

imagen63image63

143143

imagen64image64

150150

144144

151151

145145

imagen65image65

152152

imagen66image66

146146

imagen67image67

153153

imagen68image68

147147

154154

imagen69image69

55

Rex  Rex
Estructura Rex Estructura  Structure Rex Structure

155  155
Me"- /fA N-f Vnh h f3c 162 Me-f/ 1\|—-(YY^_NHa  Me "- / fA N-f Vnh h f3c 162 Me-f / 1 \ | —- (YY ^ _NHa

156  156
H fH* YiY T F.C'^^N'^N^CI 3 H 163  H fH * YiY T F.C '^^ N' ^ N ^ CI 3 H 163

157  157
1 1 Q /j t .... 1 r N-Y XNHfW HcY"/ .7 OMe 164 M6'N—1 ^rY Y>k^°:yyB H  1 1 Q / j t .... 1 r N-Y XNHfW HcY "/ .7 OMe 164 M6'N — 1 ^ rY Y> k ^ °: yyB H

158  158
*rK>Q-”‘ MU OMe 165 Me"N^ NH? H  * rK> Q- ”‘ MU OMe 165 Me "N ^ NH? H

159  159
HO. HQ"Y li yVEt OMfiH 166 ?"Y nh2 ^VT'Yr* n^AnXnAc| H  HO. HQ "Y li yVEt OMfiH 166?" Y nh2 ^ VT'Yr * n ^ AnXnAc | H

160  160
NCk ,N. .Et X j cr'N'^a 167 Me-N^N--Y^N—AY-mh Y—/ \—/ Y=rvj  NCk, N. .Et X j cr'N '^ a 167 Me-N ^ N - Y ^ N — AY-mh Y— / \ - / Y = rvj

161  161
Me'-N^ NH, N^Et n^.AnAn^ci H 168 Me-YAl-/ VM-Y~Y—NO x..-7 v../A-_,hrNo=  Me'-N ^ NH, N ^ Et n ^ .AnAn ^ ci H 168 Me-YAl- / VM-Y ~ Y — NO x ..- 7 v ../ A -_, hrNo =

[Tabla 191[Table 191

Rex  Rex
Estructura Rex Estructura  Structure Rex Structure

169  169
Y-Ny"\ NHa >jAnY.nY H 176 'fK> p \..../ \—l f3c  Y-Ny "\ NHa> jAnY.nY H 176 'fK> p \ .... / \ —l f3c

170  170
Mev P K,x-v a N{ ^ NH? k^v^oYj^Et OMeH 177 F\/~~ yvJl../yNQi f3c  Mev P K, x-v to N {^ NH? k ^ v ^ oYj ^ Et OMeH 177 F \ / ~~ yvJl ../ yNQi f3c

171  171
o"Y AAnAnYC! H 178 fYa a Y-^Y:Y0==YNYEt f3cAAnYnAc, 3 H  or "Y AAnAnYC! H 178 fYa to Y- ^ Y: Y0 == YNYEt f3cAAnYnAc, 3 H

Rex  Rex
Estructura Rex Estructura  Structure Rex Structure

172  172
..r-r'ci H 179 N > NH2 k^Nx^^O==^N5^Et H  ..r-r'ci H 179 N> NH2 k ^ Nx ^^ O == ^ N5 ^ Et H

173  173
1 ii ] H 180 / \ /r\ /—N N—f V-NH2 cFr ^—'" y=^ f3c  1 ii] H 180 / \ / r \ / —N N — f V-NH2 cFr ^ - '"y = ^ f3c

174  174
Me"N'^| NH2 N Et H 181 0 ' FaC  Me "N '^ | NH2 N Et H 181 0' FaC

175  175
Boc"^ nh2 Et ^AnA^c! H 182 cPr^N'^i ,NH2 * F.CAvAltY^C 1 3 H  Boc "^ nh2 Et ^ AnA ^ c! H 182 cPr ^ N '^ i, NH2 * F. CAvAltY ^ C 1 3 H

[Tabla 201[Table 201

Rex  Rex
Estructura Rex Estructura  Structure Rex Structure

183  183
Me,NN ,__, F3C 190 Me Me-N N-^JV-NH? . , # / Me F3C  Me, NN, __, F3C 190 Me Me-N N- ^ JV-NH? . , # / Me F3C

184  184
Me„N FaC 191 Me^__^ Me-I^ ^Ki—^ —MQa Me FaC  Me „N FaC 191 Me ^ __ ^ Me-I ^ ^ Ki— ^ —MQa Me FaC

185  185
Me2N /"I mVEt ec'^-n'^nXi 3 H 192 Me Me'N^ NH2 ^nwyyei  Me2N / "I mVEt ec '^ - n' ^ nXi 3 H 192 Me Me'N ^ NH2 ^ nwyyei

186  186
EKN'^v| - nh2 TNYEt 3 H 193 ^Yi H  EKN '^ v | - nh2 TNYEt 3 H 193 ^ Yi H

187  187
Me y hiP^Q-nh! Me FaC 194 Me"N'^] HN"OMe . xx t i H  Me and hiP ^ Q-nh! Me FaC 194 Me "N '^] HN" OMe. xx t i H

188  188
Me HN N—<7 ^N02 Me F3G 195 nh2 rrYTY'f Me"N^ ^An^N^CI w  Me HN N— <7 ^ N02 Me F3G 195 nh2 rrYTY'f Me "N ^ ^ An ^ N ^ CI w

Rex  Rex
Estructura Rex Estructura  Structure Rex Structure

189  189
Me HN^-j MeEt EX'" iX'N^ 'Cl J H 196 Me"N^ NHa ^CCVc, H  Me HN ^ -j MeEt EX '"iX'N ^' Cl J H 196 Me" N ^ NHa ^ CCVc, H

[Tabla 211[Table 211

Rex  Rex
Estructura Rex Estructura  Structure Rex Structure

197  197
Boc"n^ nh, Xa X JL F,cr^^ N N Cl ■3 H 204 ^NYA NHa ^N'ftXYEt FxX^nXXc! d H  Boc "n ^ nh, Xa X JL F, cr ^^ N N Cl ■ 3 H 204 ^ NYA NHa ^ N'ftXYEt FxX ^ nXXc! D H

198  198
Bo(>A nh, Xa X X N N XI H 205 0 x ^ rftiYr9 hf  Bo (> A nh, Xa X X N N XI H 205 0 x ^ rftiYr9 hf

199  199
Me Me on FsC'^/k'NH!, 206 B0C"N"^| ^H2 UvjY yEt Me'^^A'N'A'W^Cl H  Me Me on FsC '^ / k'NH !, 206 B0C "N" ^ | ^ H2 UvjY yEt Me '^^ A'N'A'W ^ Cl H

200  200
O i l HIM' ». i ' N N C! H 207 Me V*\ x~\ Me~N^__N4 ANH= Me CF3  O i l HIM '». I 'N N C! H 207 Me V * \ x ~ \ Me ~ N ^ __ N4 ANH = Me CF3

201  201
o V-Nv . XX a X N Cl H 208 Me S__ Me-N(N--X HO, W Me CF3  or V-Nv. XX to X N Cl H 208 Me S__ Me-N (N - X HO, W Me CF3

202  202
<v> FX'A%/1''NH2 209 Me AX MFC/^XNAnXC! h3L' H  <v> FX'A% / 1``NH2 209 Me AX MFC / ^ XNAnXC! h3L 'H

203  203
FX'^Ao, 210 Me^ Me-I^__Vj—NH2 Me  FX '^ Ao, 210 Me ^ Me-I ^ __ Vj — NH2 Me

Rex  Rex
Estructura Rex Estructura  Structure Rex Structure

211  211
Mev Me no? Me 218 rfy w yj  Mev Me not? Me 218 rfy w yj

212  212
.... N Me NH2 k/Nj.O^N Et Xl Me H 219 / y>y ^ w ^n^Yy0 F.CT^^N'^'N^CI 3 H  .... N Me NH2 k / Nj.O ^ N Et Xl Me H 219 / y> y ^ w ^ n ^ Yy0 F.CT ^^ N '^' N ^ CI 3 H

213  213
rp-i f3c'^^nhs 220 /-aCIK Me-N__Vh^\-NH2 cT  rp-i f3c '^^ nhs 220 / -aCIK Me-N__Vh ^ \ - NH2 cT

214  214
tiXy, F,C'^/'"NO;) 221 m^i\Z/n’^3^n°2 Cl  tiXy, F, C '^ /' "NO;) 221 m ^ i \ Z / n’ ^ 3 ^ n ° 2 Cl

215  215
rCK f** w M Et 3 H 222 91 B ^NY=k0=VN^Et K  rCK f ** w M Et 3 H 222 91 B ^ NY = k0 = VN ^ Et K

216  216
O NH, Me''N"k " N ' m"‘ C‘ H 223 O0lXx F3C''^'NH2  O NH, Me''N "k" N 'm "‘ C ‘H 223 O0lXx F3C' '^' NH2

217  217
fCH ^ XCX F:jC^^ NH? 224 CX F,C/^;;:>''"'N02  fCH ^ XCX F: jC ^^ NH? 224 CX F, C / ^ ;;:> '' "'N02

[Tabla 231[Table 231

Rex  Rex
Estructura Rex Estructura  Structure Rex Structure

225  225
yvy WV^^o=^NyEt 'Cl 3 H 232 NH? Et2N'^^0vX|°'^ISiVJEt kk^k^A^ H  yvy WV ^^ o = ^ NyEt 'Cl 3 H 232 NH? Et2N '^^ 0vX | °' ^ ISiVJEt kk ^ k ^ A ^ H

226  226
Bocy^ nh2 k^N^nX^N^-Et Meok^k'-y'. A H 233 rY0rt"YNrB H  Bocy ^ nh2 k ^ N ^ nX ^ N ^ -Et Meok ^ k'-y '. A H 233 rY0rt "YNrB H

227  227
ff^i T> Xn^oXm Et ° XXX&, H 234 Me-N^JM^^KNH2 Aert  ff ^ i T> Xn ^ oXm Et ° XXX &, H 234 Me-N ^ JM ^^ KNH2 Aert

228  228
b°c-iO^O^NHz f3c 235 Me"N^ NHj L Ji jP J Ac-iy^N Nul H H  b ° c-iO ^ O ^ NHz f3c 235 Me "N ^ NHj L Ji jP J Ac-iy ^ N Nul H H

Rex  Rex
Estructura Rex Estructura  Structure Rex Structure

229  229
Boc-i\( —ry^a f3c 236 Me_NCyNHp^NH2 HN ,0 X O' Me  Boc-i \ (—ry ^ a f3c 236 Me_NCyNHp ^ NH2 HN, 0 X O 'Me

230  230
Boc"n-^ ^ F.C'^^N'^'NT^CI 3 H 237 / \ ff Me~r^__^N—y y-N02 hn; yo S'' 0'' Me  Boc "n- ^ ^ F.C '^^ N' ^ 'NT ^ CI 3 H 237 / \ ff Me ~ r ^ __ ^ N — and y-N02 hn; I S' '0' 'Me

231  231
nh2 Me^N^ y^N^N^cl Me H 238 l' i ^2 L ill HN .■N'""'N CI oy-o H Me  nh2 Me ^ N ^ y ^ N ^ N ^ cl Me H 238 l 'i ^ 2 L ill HN. ■ N' "" 'N CI oy-o H Me

[Tabla 241[Table 241

Rex  Rex
Estructura Rex Estructura  Structure Rex Structure

239  239
Me_KZ/^Zy^Nh- Ph 246 *1 B%-O0H H V7 Et  Me_KZ / ^ Zy ^ Nh- Ph 246 * 1 B% -O0H H V7 Et

240  240
N02 Ph 247 *2 / \ OH h2m.\Y x—/ Et HCI  N02 Ph 247 * 2 / \ OH h2m. \ Y x— / Et HCI

241  241
Me-N^y-/~i^NOs \ 248 *1 B“VfA;0H H \_/\t  Me-N ^ y- / ~ i ^ NOs \ 248 * 1 B “VfA; 0H H \ _ / \ t

242  242
^Y^°=VlvEt H 249 *2 hsn-/~y0H X—7 Et HCI  ^ Y ^ ° = VlvEt H 249 * 2 hsn- / ~ y0H X — 7 Et HCI

243  243
Me—N—^ —NH2 Me-N V Ac 250 *3 Bocv /—\ OH K-<X  Me — N— ^ —NH2 Me-N V Ac 250 * 3 Bocv / - \ OH K- <X

244  244
Me-Nvyv-p^N°2 Me— An 251 *4 ^0H x—/ iPr HC!  Me-Nvyv-p ^ N ° 2 Me— An 251 * 4 ^ 0H x— / iPr HC!

245  245
M0'N'^| nh2 =yN^Et Me^NA;i/v.NJ^NA.c! Ac H 252 *3 Boc /—v OH K-OiPr  M0'N '^ | nh2 = yN ^ Et Me ^ NA; i / v.NJ ^ NA.c! Ac H 252 * 3 Boc / —v OH K-OiPr

55

Rex  Rex
Estructura Rex Estructura  Structure Rex Structure

253 *4  253 * 4
/—\ OH 2 'iPr HCI 260 Me- K^/N^(^N'^y3^NH2 HN 'Ac  / - \ OH 2 'iPr HCI 260 Me- K ^ / N ^ (^ N' ^ y3 ^ NH2 HN 'Ac

254  254
Ue i cX X\r m. 1 * Aow* qiJUL IX Me^h K N Cl 261 A "A / \ Me-N N..( N-f V-NCL \__/ \__/ y=/ HN \ Ac  Ue cX X \ r m. 1 * Aow * qiJUL IX Me ^ h K N Cl 261 A "A / \ Me-N N .. (N-f V-NCL \ __ / \ __ / y = / HN \ Ac

255  255
Boc''-f\r''~"A \ X_yN' y=/1m* Me 262 HN Ac  Boc '' - f \ r '' ~ "A \ X_yN 'y = / 1m * Me 262 HN Ac

256  256
Boc H 263 Me-.N^ NH2 k^N^O^hyEt Ac—N "Ci H H  Boc H 263 Me-.N ^ NH2 k ^ N ^ O ^ hyEt Ac — N "Ci H H

257  257
toc'fOi_H^"i=^NH2 Me 264 mo"OXXs,X3“nh> Me-rv( Ac  toc'fOi_H ^ "i = ^ NH2 Me 264 m or" OXXs, X3 "nh> Me-rv (Ac

258  258
Me 265 Me-N__X_X^N^3^N°2 Me-N Ac  Me 265 Me-N__X_X ^ N ^ 3 ^ N ° 2 Me-N Ac

259  259
°OX3no= Me 266 ^ny^x° rNvEt mxM/Ai Ac H  ° OX3no = Me 266 ^ ny ^ x ° rNvEt mxM / Ai Ac H

[Tabla 261[Table 261

Rex  Rex
Estructura Rex Estructura  Structure Rex Structure

267  267
Me_x__^"^3”"^ cPr 274 m^33mv3_nh2 HN^O Me  Me_x __ ^ "^ 3” "^ cPr 274 m ^ 33mv3_nh2 HN ^ O Me

268  268
Me-tQ-p_N°2 cPr 275 Me-N7 XN-m^X~N02 HNT^O Me  Me-tQ-p_N ° 2 cPr 275 Me-N7 XN-m ^ X ~ N02 HNT ^ O Me

269  269
MevN'"x: NK, k^M^^O-Jy.w.Et cPr H 276 Mekn'''x nh2 k^N^^O^yN^Et N^CI Me 0 H  MevN '"x: NK, k ^ M ^^ O-Jy.w.Et cPr H 276 Mekn' '' x nh2 k ^ N ^^ O ^ yN ^ Et N ^ CI Me 0 H

270  270
/Y°XX 277 Me-N^N^^^~V-NH2 °^S--0 Me,N  / Y ° XX 277 Me-N ^ N ^^^ ~ V-NH2 ° ^ S - 0 Me, N

Rex  Rex
Estructura Rex Estructura  Structure Rex Structure

271  271
XT°rx 278 Me—N^\l—(^^N——N02 W o,sC Me?N  XT ° rx 278 Me — N ^ \ l - (^^ N —— N02 W o, sC Me? N

272  272
^H2 XWc w H 279 o=k \]—^ yNOj 0-S=O Me0N  ^ H2 XWc w H 279 o = k \] - ^ yNOj 0-S = O Me0N

273  273
k^N.^OpKL^Et °, L 1 11 T Me N 0 H 280 nh2 vNyxOp Et o, L j! III Me3N o H  k ^ N. ^ OpKL ^ Et °, L 1 11 T Me N 0 H 280 nh2 vNyxOp Et o, L j! III Me3N or H

[Tabla 271[Table 271

Rex  Rex
Estructura Rex Estructura  Structure Rex Structure

281  281
oJ^ ,'S-0 Me-N H 288 >V-Vpr r j o  oJ ^, 'S-0 Me-N H 288> V-Vpr r j o

282  282
Me-t/ VN02 P-o Me-N H 289 0 i! /W'SriPr ■1 T 'o  Me-t / VN02 P-o Me-N H 289 0 i! / W'SriPr ■ 1 T 'or

283  283
Me^N NHa ^NN;^0Xi'W'Et %Xyk, Me-N No H H 290 “V^ Y ^N°2 jprs  Me ^ N NHa ^ NN; ^ 0Xi'W'Et% Xyk, Me-N No H H 290 “V ^ Y ^ N ° 2 jprs

284  284
Me _K^3J"",v3t_NH2 Me2N^0 291 W>*9 Iv^iPr y 0 Me  Me _K ^ 3J "", v3t_NH2 Me2N ^ 0 291 W> * 9 Iv ^ iPr and 0 Me

285  285
Me-l/ \|—P —[vjQ2 Wle2N^O 292 Me,.,-,;Jr-iPr C 'X 0 ^Sjh9  Me-l / \ | —P - [vjQ2 Wle2N ^ O 292 Me,., -,; Jr-iPr C 'X 0 ^ Sjh9

286  286
Me"N^ NH2 XXIX 6 H 293 ^C! I O A X y^N'^!\r''SiV!e 0=^=0 H iPr  Me "N ^ NH2 XXIX 6 H 293 ^ C! I O A X and ^ N '^! \ R''SiV! E 0 = ^ = 0 H iPr

287  287
Me ipr^ 294 CjXXx y^N^N-^SMe 3-S^O H iPr  I ipr ^ 294 CjXXx and ^ N ^ N- ^ SMe 3-S ^ O H iPr

RexRex

EstructuraStructure

RexRex

EstructuraStructure

295295

imagen70image70

302302

imagen71image71

296296

303303

imagen72image72

297297

imagen73image73

304304

imagen74image74

298298

305305

imagen75image75

299299

imagen76image76

306306

300300

imagen77image77

307307

301301

imagen78image78

308308

imagen79image79

[Tabla 291[Table 291

Rex  Rex
Estructura Rex Estructura  Structure Rex Structure

309  309
NH, ci rrfa N'VSms O H 317 Mev^° irV N^'N'''xN^SMe H  NH, ci rrfa N'VSms O H 317 Mev ^ ° irV N ^ 'N' '' xN ^ SMe H

310  310
nh2q rf‘ft Me2N^J^ANANASMe O H 318 Cl fjJIH2 OMe Y^N n^An^n^smb N  nh2q rf‘ft Me2N ^ J ^ ANANASMe O H 318 Cl fjJIH2 OMe Y ^ N n ^ An ^ n ^ smb N

311  311
- rf^ A. ^ Me Me T K N § O M O 319 Ci MH2 o X qa X O FT N.vi A X, ^ N N SMe H  - rf ^ A. ^ Me Me T K N § O M O 319 Ci MH2 or X qa X O FT N.vi A X, ^ N N SMe H

Rex  Rex
Estructura Rex Estructura  Structure Rex Structure

312  312
nh2 o rTi H N A- X Jl A 2 NASMo o H 320 NH20 -0=1 X o YY rNH Et "Q H  nh2 or rTi H N A- X Jl A 2 NASMo or H 320 NH20 -0 = 1 X or YY rNH Et "Q H

313  313
nh2C| 9 11 X X H„N~S N N SMe 2 ^ h O n 321 ^0 -coX X o Hi iPr.S'^^N'^'N^SMe O H  nh2C | 9 11 X X H „N ~ S N N SMe 2 ^ h O n 321 ^ 0 -coX X or Hi iPr.S '^^ N' ^ 'N ^ SMe O H

314  314
NH3p 9rfY" H2N-SA^'-N YA'SMe 0 H 322 nh2ci o noY 11 A.A A <x KKS A M N SMe Me2N ^ h  NH3p 9rfY "H2N-SA ^ '- N YA'SMe 0 H 322 nh2ci or noY 11 A.A A <x KKS A M N SMe Me2N ^ h

315  315
NH; C| orf\S 11 n. n <x N SMe Et 'q H 323 0 A2 Cl ,.--v Y-. -X. - M N SMe H  NH; C | orf \ S 11 n. n <x N SMe Et 'q H 323 0 A2 Cl, .-- v Y-. -X. - M N SMe H

316  316
yH,oi r^fSYN iPr.sJ^J-.NANASMe no H 324 A* Cl rTt FN HN XANAN^SMe o H  yH, oi r ^ fSYN iPr.sJ ^ J-.NANASMe no H 324 A * Cl rTt FN HN XANAN ^ SMe or H

[Tabla 301[Table 301

Rex  Rex
Estructura Rex Estructura  Structure Rex Structure

325  325
nh2o o ffYf MeJM - S'N ' A" SMe b H 333 A.CI AX o 1 \ I I ,S, N N SMe FqC b H  nh2o or ffYf MeJM - S'N 'A "SMe b H 333 A.CI AX or 1 \ I I, S, N N SMe FqC b H

326  326
T2CI h o rfii N SMe o " 334 nh20 0=\ [1 Y ^A Y nh hiaX^A. A A oiji Y N N SMe O H  T2CI h or rfii N SMe or "334 nh20 0 = \ [1 Y ^ A Y nh hiaX ^ A. A A oiji Y N N SMe O H

327  327
NH2 9 h iiJL 1 A A N - S N N SMe Ms o H 335 cf3 m2o 1^1° l! NH HiN'AAl'iAsMe o H  NH2 9 h iiJL 1 A A N - S N N SMe Ms or H 335 cf3 m2 or 1 ^ 1 ° l! NH HiN'AAl'iAsMe or H

328  328
NHa Cj Ab Yf ll 'N v-N^Av.ANANASMe o H 336 T29 r-\ [[ A A H  NHa Cj Ab Yf ll 'N v-N ^ Av.ANANASMe or H 336 T29 r- \ [[A A H

329  329
CFS Cl xSr[Y^n H3NyVbNANASMe O H 337 j1H2 CMe "VfV? n^A a a. NASMe H  CFS Cl xSr [Y ^ n H3NyVbNANASMe O H 337 j1H2 CMe "VfV? N ^ A a a. NASMe H

330  330
NHaCl MeO_ ,^°A A., 1 H A N^-NANA,gMe H 338 oA I q J YH 'S n ^ lA" SMe A "o H  NHaCl MeO_, ^ ° A A., 1 H A N ^ -NANA, gMe H 338 oA I q J YH 'S n ^ lA "SMe A" or H

Rex  Rex
Estructura Rex Estructura  Structure Rex Structure

331  331
h’n YVtV H 339 Ao MeC H  h’n YVtV H 339 Ao MeC H

332  332
A Cl n. A A ^ N N SMe H 340 NH, J 2 OAc ™ A vi NA'N-^N^VgMe H  A Cl n. A A ^ N N SMe H 340 NH, J 2 OAc ™ A vi NA'N- ^ N ^ VgMe H

[Tabla 311[Table 311

RexRex

EstructuraStructure

RexRex

EstructuraStructure

341341

imagen80image80

348348

imagen81image81

342342

349349

imagen82image82

343343

imagen83image83

350350

imagen84image84

344344

imagen85image85

351351

imagen86image86

3453. 4. 5

imagen87image87

352352

imagen88image88

346346

imagen89image89

353353

imagen90image90

347347

imagen91image91

354354

imagen92image92

Rex  Rex
Estructura Rex Estructura  Structure Rex Structure

355  355
^OAc A, , A-._ y N N SMe Ph H 363 nh20 ^v.0 A. P. F Yi NV^N'^'N;^'SMe Cl H  ^ OAc A,, A -._ and N N SMe Ph H 363 nh20 ^ v.0 A. P. F Yi NV ^ N '^' N; ^ 'SMe Cl H

356  356
^H2 Cl riV? NV^N^N^SMe Cl H 364 Me jHs9 /|Yr ™ SMe  ^ H2 Cl riV? NV ^ N ^ N ^ SMe Cl H 364 Me jHs9 / | Yr ™ SMe

357  357
fa OAc clAt Ft N K .fA 0,j ^ N N SMe H 365 nh3 Cl F3CYYf Y^n N^LNANASMe H  fa OAc clAt Ft N K .fA 0, j ^ N N SMe H 365 nh3 Cl F3CYYf Y ^ n N ^ LNANASMe H

358  358
faO ll WH NV”A nAms Ph H 366 ^OAC N'"^N A^SMe H  faO ll WH NV ”A nAms Ph H 366 ^ OAC N '" ^ N A ^ SMe H

359  359
Me NH„ pi AV. N^A'N'XN^SMe H 367 Cl fa Cl X o=\ i ni y> NYA’M'A'N^VSMe Cl H  I NH „pi AV. N ^ A'N'XN ^ SMe H 367 Cl fa Cl X o = \ i ni y> NYA’M'A'N ^ VSMe Cl H

360  360
nh2 MeO =\, Et H 368 ci nh2 qAc N T £l N^SMe Cl H  nh2 MeO = \, Et H 368 ci nh2 qAc N T £ l N ^ SMe Cl H

361  361
NH2OAc AA NY^'N'^'N<'^SMe Ci H 369 Cl faO AAV V^M^N^'SMe Ai H  NH2OAc AA NY ^ 'N' ^ 'N <' ^ SMe Ci H 369 Cl faO AAV V ^ M ^ N ^ 'SMe Ai H

362  362
NHz0 NA^NANASMe H 370 To FiVfyV tApMe  NHz0 NA ^ NANASMe H 370 To FiVfyV tApMe

[Tabla 331[Table 331

Rex  Rex
Estructura Rex Estructura  Structure Rex Structure

371  371
r^ci rXA P N N SMe Ph H 379 fa Yf q>JL Jl I 1 ;s^nanaci Me 'q H  r ^ ci rXA P N N SMe Ph H 379 fa Yf q> JL Jl I 1; s ^ nanaci Me 'q H

372  372
NH, 1 2 OAc fNfVN Y^N^N^SMe Ph H 380 YOAc CIA° FV H  NH, 1 2 OAc fNfVN Y ^ N ^ N ^ SMe Ph H 380 YOAc CIA ° FV H

373  373
faO .f\L Q=\ A wCa Y N N SMe Ph H 381 Br f * OAc a°y» N^AN^NAsMe H  faO .f \ L Q = \ A wCa Y N N SMe Ph H 381 Br f * OAc a ° y »N ^ AN ^ NAsMe H

Rex  Rex
Estructura Rex Estructura  Structure Rex Structure

374  374
^H2Ci N N-^NANASMe R 382 Y2 OAc Yf NY-NYNYSMe H  ^ H2Ci N N- ^ NANASMe R 382 Y2 OAc Yf NY-NYNYSMe H

375  375
Br ^HjCI YYX N'::^N'^Y'''SMe H 383 Cl NH2 OAc crri N N N SMe H  Br ^ HjCI YYX N ':: ^ N' ^ Y '' 'SMe H 383 Cl NH2 OAc crri N N N SMe H

376  376
Cl Cl A0 yd N N N SMe H 384 Cl ^ OAc dx? '^-ANAN*~'SMe H  Cl Cl A0 yd N N N SMe H 384 Cl ^ OAc dx? '^ -ANAN * ~' SMe H

377  377
Ci ^ci X.. X. N N SMe H 385 CFS NHsq VfVV n^S/nAsm. H  Ci ^ ci X .. X. N N SMe H 385 CFS NHsq VfVV n ^ S / nAsm. H

378  378
f. ^H2c! dry** w-Y-N-YvN^gMe H 386 Br NH*0 1 o=A I r "Y Y^nh NY^NYN^SMe H  F. ^ H2c! dry ** w-Y-N-YvN ^ gMe H 386 Br NH * 0 1 o = A I r "Y Y ^ nh NY ^ NYN ^ SMe H

[Tabla 341[Table 341

Rex  Rex
Estructura Rex Estructura  Structure Rex Structure

387  387
N^O aTVV NiYvN''V|Y'SMe H 395 Me NH2 J\°Ynyb N^ANYNYCi H  N ^ O aTVV NiYvN''V | Y'SMe H 395 Me NH2 J \ ° Ynyb N ^ ANYNYCi H

388  388
Cl Xo cor N N N SMe H 396 nh2 x^d-N^Et Y 'Ci o=s=qh 1 Me  Cl Xo cor N N N SMe H 396 nh2 x ^ d-N ^ Et Y 'Ci o = s = qh 1 Me

389  389
Cl NH2 0 nJ^Ynh YYN^NYSMe H 397 p nh2 ° d lx NCl H  Cl NH2 0 nJ ^ Ynh YYN ^ NYSMe H 397 p nh2 ° d lx NCl H

390  390
nh2 0° lfNYB A'A N' N G! H 398 O h.n\Vp' ‘ X Y cr iOci  nh2 0 ° lfNYB A'A N 'N G! H 398 O h.n \ Vp '‘X Y cr iOci

391  391
NHn o rfVv* Me o H 399 . Me H„N-/ Y _ 2 \__/ |yj-E0C H  NHn or rfVv * Me or H 399. Me H „N- / Y _ 2 \ __ / | yj-E0C H

392  392
0 m2 Me. 'Y 0J aK. o-VTA CI'^^^N N^CI H 400 /—\ Me h2n-< X '—' NH2 2HCI  0 m2 Me. 'And 0J aK. o-VTA CI '^^^ N N ^ CI H 400 / - \ Me h2n- <X' - 'NH2 2HCI

Rex  Rex
Estructura Rex Estructura  Structure Rex Structure

393  393
NK, QWc, ; H SMr 401 m2 N^'Ci H  NK, QWc; H SMr 401 m2 N ^ 'Ci H

394  394
nh2 MeS^-^O^k .N„ -Et XXII ^ N N Cl H 402 Cl ^Hs XfVrB H  nh2 MeS ^ - ^ O ^ k .N „-Et XXII ^ N N Cl H 402 Cl ^ Hs XfVrB H

[Tabla 35]  [Table 35]

Rex  Rex
Estructura Rex Estructura  Structure Rex Structure

403  403
NSi, Oy\0\NYEt OsWa H 411 YNrEt H  NSi, Oy \ 0 \ NYEt OsWa H 411 YNrEt H

404  404
nh2 h 412 ^~N02 MeO  nh2 h 412 ^ ~ N02 MeO

405  405
nh2 ttrtY H 413 b"^CA>n^ MeO  nh2 ttrtY H 413 b "^ CA> n ^ MeO

406  406
^N"Me 414 Me'N^ NH k^N^N^CI H  ^ N "Me 414 Me'N ^ NH k ^ N ^ N ^ CI H

407  407
H2NY^r-0Me N k^N Me 415 Mo OMeH  H2NY ^ r-0Me N k ^ N Me 415 Mo OMeH

408  408
NH, nPr MeO " "■ Nn'"XI H 416 NH2 Me ^YTyV^ ^^'N^'N'^CI H  NH, nPr MeO "" ■ Nn '"XI H 416 NH2 Me ^ YTyV ^ ^^' N ^ 'N' ^ CI H

409  409
nh2 Af^/^nPr Ph'^^'N'^N^CI H 417 M6'0 NHS CH, ^^'N'^'N^CI H  nh2 Af ^ / ^ nPr Ph '^^' N '^ N ^ CI H 417 M6'0 NHS CH, ^^' N '^' N ^ CI H

410  410
nh2 X^N^Et Me-A T 1 J T H 418 Ti NH, ^XTlY H  nh2 X ^ N ^ Et Me-A T 1 J T H 418 Ti NH, ^ XTlY H

Rex  Rex
Estructura Rex Estructura  Structure Rex Structure

419  419
80C'O s«, rfxx ^i\T N Cl H 426 Me-h/ \i— / f3c  80C'O s «, rfxx ^ i \ T N Cl H 426 Me-h / \ i— / f3c

420  420
NHa ij H HCi 427 Me"N^j NHS k/NY^^0=VNY'Et MeO'^T^N'^'-rsl^CI H  NHa ij H HCi 427 Me "N ^ j NHS k / NY ^^ 0 = VNY'Et MeO '^ T ^ N' ^ '- rsl ^ CI H

421  421
OEt 428 ?"T ^ <^YfYr* ^X'N-TNXCi H  OEt 428? "T ^ <^ YfYr * ^ X'N-TNXCi H

422  422
OEt 429 TT ^ OV\°Vva T ii T T H  OEt 429 TT ^ OV \ ° Vva T ii T T H

423  423
M6'N^ NH2 Till MeO^N N Cl H 430 ; jxr  M6'N ^ NH2 Till MeO ^ N N Cl H 430; jxr

424  424
MesN^ m2 '^XtxY 3 H 431 ^Cl r3 jpT"NY° 0?N'XX'0^'  MonthN ^ m2 '^ XtxY 3 H 431 ^ Cl r3 jpT "NY ° 0? N'XX'0 ^'

425  425
BoCs, ■, I., N Y NH2 H 432 Me £> JXf  BoCs, ■, I., N AND NH2 H 432 Me £> JXf

[Tabla 371[Table 371

Rex  Rex
Estructura Rex Estructura  Structure Rex Structure

433  433
NMe rN-J rJ fvV0 440 Mc'n^ ^iV'ni ^ Ye  NMe rN-J rJ fvV0 440 Mc'n ^ ^ iV'ni ^ Ye

434  434
Me T 'w Y xV H,nTT0^ 441 0 Bn0~f //~\ r-\  Me T 'w Y xV H, nTT0 ^ 441 0 Bn0 ~ f // ~ \ r- \

Rex  Rex
Estructura Rex Estructura  Structure Rex Structure

435  435
H^N-^^Cr 442 Cp3 j"* Ih°h NT,Et r^'w '^sN'^srr^ci mY "  H ^ N - ^^ Cr 442 Cp3 j "* Ih ° h NT, Et r ^ 'w' ^ sN '^ srr ^ ci mY"

436  436
f3c 443 ^""O 7H* H  f3c 443 ^ "" O 7H * H

437  437
nh2 MeO'^^A'N>^N^CI H 444 OMe Me-t/ Vl—7X w M NO,  nh2 MeO '^^ A'N> ^ N ^ CI H 444 OMe Me-t / Vl — 7X w M NO,

438  438
0 BY-/yO-B“ H \^zj V-.../ 445 OMe \ NH?  0 BY- / yO-B “H \ ^ zj V -... / 445 OMe \ NH?

439  439
NH, ; h Me' ^ 446 NH„ / ^ Br^^N^Yxi H  NH,; h Me '^ 446 NH „/ ^ Br ^^ N ^ Yxi H

[Tabla 381  [Table 381

Rex  Rex
Estructura Rex Estructura  Structure Rex Structure

447  447
OMe NH2 M . N . ,'• H Me 454 /—v /=\ y—OBn Boc~VYy)“H MeO  OMe NH2 M. N. , '• H Me 454 / —v / = \ y — OBn Boc ~ VYy) “H MeO

448  448
0 Bn07C>-OX>“ 455 0 / \ /=\ y-QBn Hi .. )—(k... MeC>  0 Bn07C> -OX> “455 0 / \ / = \ y-QBn Hi ..) - (k ... MeC>

449  449
H2N~<^^— 456 ^ CF OjN'^^^N'Y  H2N ~ <^^ - 456 ^ CF OjN '^^^ N'Y

450  450
NH,, ^Yjy\OYVB H 457 jOY L>E ^ Me  NH ,, ^ Yjy \ OYVB H 457 jOY L> E ^ Me

451  451
<p^O”iOHMe OaN 458 nh2 X 1 1 1 N J H Me' ^  <p ^ O ”iOHMe OaN 458 nh2 X 1 1 1 N J H Me '^

Rex  Rex
Estructura Rex Estructura  Structure Rex Structure

452  452
<^f“Nv_^NwN-Me H2N 459 ~ "y~N\ )N~Me 0 ^-OMe  <^ f “Nv_ ^ NwN-Me H2N 459 ~" and ~ N \) N ~ Me 0 ^ -OMe

453  453
nh2 ffyy* r^N'^^N^tvT'CI I 1 H 460 0 ^—OMe  nh2 ffyy * r ^ N '^^ N ^ tvT'CI I 1 H 460 0 ^ —OMe

[Tabla 391[Table 391

Rex  Rex
Estructura Rex Estructura  Structure Rex Structure

461  461
Me A NK, 1 H OMr 468 Me~C^P^NH2 Met)  Me A NK, 1 H OMr 468 Me ~ C ^ P ^ NH2 Met)

462  462
MeO 0 0Bn H, 469 MeO  MeO 0 0Bn H, 469 MeO

463  463
MeO HN )—(\ /) \—/ 0Bn Hi, 470 MeVA NH2 kA^oA^Kya MeO-^^N^N^XI H  MeO HN) - (\ /) \ - / 0Bn Hi, 470 MeVA NH2 kA ^ oA ^ Kya MeO - ^^ N ^ N ^ XI H

464  464
0 ,., ■.—,,,. r.. \ y OBn Me-f{_Vy/-[i MeO 471 N > NK, l A ,^0=\ W Et jfl T T H  0,., ■ .— ,,,. r .. \ and OBn Me-f {_Vy / - [i MeO 471 N> NK, l A, ^ 0 = \ W Et jfl T T H

465  465
0, _ ,__„ VOBrs MeQ/ 472 Q f^l Me'V°x^xNA-^kN02 0 Me  0, _, __ „VOBrs MeQ / 472 Q f ^ l Me'V ° x ^ xNA- ^ kN02 0 Me

466  466
rn jVS --v 473 Me"N^ ^ Me  rn jVS --v 473 Me "N ^ ^ Me

467  467
fYN) 474 MV^ jfA ! £ Me  fYN) 474 MV ^ jfA! £ me

Rex  Rex
Estructura Rex Estructura  Structure Rex Structure

475  475
K>Q NOa 482 Me- -N)-tC yy ) \_/ V_y V_^ OBn hH H Q  K> Q NOa 482 Me- -N) -tC yy) \ _ / V_y V_ ^ OBn hH H Q

476  476
Me „ f”. ^ n IT a_nAci Me 483 Me<3 Me-vbcyy 0Bn ri o  I "f". ^ n IT a_nAci Me 483 Me <3 Me-vbcyy 0Bn ri o

477  477
HO /—, ^ x-o-o \ NHp 484 Me-lb^N(^HQ nh2  HO / -, ^ x-o-o \ NHp 484 Me-lb ^ N (^ HQ nh2

478  478
0Bn H 485 Cl nh3 M° ifV0 ^■N'^^NAN-A.C| H  0Bn H 485 Cl nh3 M ° ifV0 ^ ■ N '^^ NAN-A.C | H

479  479
his/ wy N—' ^^ OBn H 'o 486 MeO Me-Nfy>-N/™y-y_') \__/ \_/ _y NH?  his / wy N— '^^ OBn H' or 486 MeO Me-Nfy> -N / ™ and-y_ ') \ __ / \ _ / _y NH?

480  480
Me N y—^ y N----7 ^—{ OBn ni> 487 nh2 MeO. ^\0=yN. .Et rXQX ,.N J H  Me N y— ^ y N ---- 7 ^ - {OBn ni> 487 nh2 MeO. ^ \ 0 = yN. .Et rXQX, .N J H

481  481
nh2 Me-N^)—<^J> 488 nh2 r-MXk .6 H Me  nh2 Me-N ^) - <^ J> 488 nh2 r-MXk .6 H Me

[Tabla 41][Table 41]

Rex  Rex
Estructura Rex Estructura  Structure Rex Structure

489  489
nh2 Me0^^o=yN Et r^'YN^J H Me^-J 496 Me rrV^  nh2 Me0 ^^ o = yN Et r ^ 'YN ^ J H Me ^ -J 496 Me rrV ^

490  490
isih2 YY0=VN^Et r'-y^-SibA, rr^ H ,N.J Me 497 0- J 2 OH  isih2 YY0 = VN ^ Et r'-y ^ -SibA, rr ^ H, N.J Me 497 0- J 2 OH

491  491
nh2 ^\0=<.,tYEt 498 Me HjNyyrN^ ^N'Me  nh2 ^ \ 0 = <., tYEt 498 Me HjNyyrN ^ ^ N'Me

Rex  Rex
Estructura Rex Estructura  Structure Rex Structure

492  492
°0~Q no2 499 r^N'^^-NO, <°kk Vo  ° 0 ~ Q no2 499 r ^ N '^^ - NO, <° kk Vo

493  493
OaN V-N Boc 500 nh2 "V> .•'V^.AXci M i J H Me  OaN V-N Boc 500 nh2 "V>. • 'V ^ .AXci M i J H Me

494  494
Me rYn OpN k^NH 501 nh2 {°4k h V-0  I rYn OpN k ^ NH 501 nh2 {° 4k h V-0

495  495
MeCk ^ Y^X r' N ''--"N02 n! i: 2 \,o^J 502 Xk N0>  MeCk ^ Y ^ X r 'N' '- "N02 n! I: 2 \, or ^ J 502 Xk N0>

[Tabla 421[Table 421

Rex  Rex
Estructura Rex Estructura  Structure Rex Structure

503  503
j^N'^^'NOz nr^ 509 NH? MeO^okN Et : j} | T 1 ■ H  j ^ N '^^' NOz nr ^ 509 NH? MeO ^ okN Et: j} | T 1 ■ H

504  504
MeO^^ r^'N''kk'-NH l 1 r'-yv^- 510 Plp^NO., 0^j  MeO ^^ r ^ 'N''kk'-NH l 1 r'-yv ^ - 510 Plp ^ NO., 0 ^ j

505  505
nh2 iYl°kfNkB H 511 Mfk-k  nh2 iYl ° kfNkB H 511 Mfk-k

506  506
Me 6 f ^ k ^pyN^Et " CT f'Xlsf^'CI H 512 “eH pp^ nh2 r^w-kk  Me 6 f ^ k ^ pyN ^ Et "CT f'Xlsf ^ 'CI H 512“ eH pp ^ nh2 r ^ w-kk

507  507
0 N NH2 i xnv O -^ N N Cl H 513 nh2 Et r^N-^kNkNk ^ X J H f N McX'k  0 N NH2 i xnv O - ^ N N Cl H 513 nh2 Et r ^ N- ^ kNkNk ^ X J H f N McX'k

RexRex

EstructuraStructure

RexRex

EstructuraStructure

508508

imagen93image93

514514

imagen94image94

[Tabla 43[Table 43

RexRex

EstructuraStructure

RexRex

EstructuraStructure

515515

imagen95image95

521521

imagen96image96

516516

imagen97image97

522522

imagen98image98

517517

imagen99image99

523523

imagen100image100

518518

imagen101image101

524524

imagen102image102

519519

imagen103image103

525525

imagen104image104

520520

imagen105image105

526526

imagen106image106

Rex  Rex
Estructura Rex Estructura  Structure Rex Structure

527  527
f \ Me-N^__/N 1 ^ H 532 iyte S nh2 CdXXnaX H  f \ Me-N ^ __ / N 1 ^ H 532 iyte S nh2 CdXXnaX H

528  528
Pule u S cyN^^p-fyhyEt H 533 ^y\ °2MY^'iMY'0  Poll u S cyN ^^ p-fyhyEt H 533 ^ and \ ° 2MY ^ 'iMY'0

529  529
0 N s ^ °YNYr'f*SrVEt H 534 °^yvIV0 '‘■■'O''  0 N s ^ ° YNYr'f * SrVEt H 534 ° ^ yvIV0 '‘■■' O ''

530  530
r° r iV) 535 ^N'Me h^v'Vt’0  r ° r iV) 535 ^ N'Me h ^ v'Vt’0

531  531
d~k \__t ^ S r* ^Y?vp=JYN^a H 536 NH, r°rr¥vEt 0^"-N"^-" N-'"-N^'-CI / " f'Y m,'<0  d ~ k \ __ t ^ S r * ^ Y? vp = JYN ^ a H 536 NH, r ° rr ¥ vEt 0 ^ "- N" ^ - "N - '" - N ^' - CI / "f'Y m, '<0

[Tabla 451[Table 451

Rex  Rex
Estructura Rex Estructura  Structure Rex Structure

537  537
n ■%i'•■■-' 542 Me^ 1 i  n ■% i '• ■■ -' 542 Me ^ 1 i

538  538
k“"'o H"'air° 543 M8"N'^N 0 H  k "" 'or H "' air ° 543 M8" N '^ N 0 H

Rex  Rex
Estructura Rex Estructura  Structure Rex Structure

539  539
nh2 x0xfyY /’ " C) 544 k N XXO N ^ Til 1 T Me H  nh2 x0xfyY / ’" C) 544 k N XXO N ^ Til 1 T Me H

540  540
Me.N^ t*. 1 i,c, H 545 On y^YYiPr H  Me.N ^ t *. 1 i, c, H 545 On and ^ YYiPr H

541  541
Me^ i ji 'NO, 546 ^NT^'1 M M 0 H^C T. N vJ'k^ N^ Me UL X 1 ^ U N Cl H  Me ^ i ji 'NO, 546 ^ NT ^' 1 M M 0 H ^ C T. N vJ'k ^ N ^ Me UL X 1 ^ U N Cl H

[Tabla 461[Table 461

Rex  Rex
Estructura Rex Estructura  Structure Rex Structure

547  547
N ^ L^'N''T^0 w .. O Me H 552 N P  N ^ L ^ 'N''T ^ 0 w .. O Me H 552 N P

548  548
O k/NT^yN Et F^^N^N^CI H 553 Me"N-^j ^'N^'N'^0 o li N a TfY jf T M  O k / NT ^ yN Et F ^^ N ^ N ^ CI H 553 Me "N- ^ j ^ 'N ^' N '^ 0 or li N a TfY jf T M

549  549
Me'N"0 ^ O H N 9 Me\OH H 554 M>-Y <V'A^ k-Nyr\ F-^NO,  Me'N "0 ^ O H N 9 Me \ OH H 554 M> -Y <V'A ^ k-Nyr \ F- ^ NO,

550  550
Me"N'0 ^NT^^N^iPr ,.-T JL >1 -,--- F N N Cl H 555 ‘"Op F NH,  Me "N'0 ^ NT ^^ N ^ iPr, .- T JL> 1 -, --- F N N Cl H 555‘ "Op F NH,

551  551
Me"N-^0 k.N 556 Me-N-P n'O O k.Nj?NX.^YEt H  Me "N- ^ 0 k.N 556 Me-N-P n'O O k.Nj? NX. ^ YEt H

Rex  Rex
Estructura  Structure

557  557
MeO'^^NOj,  MeO '^^ NOj,

558  558

559  559
Me'N^, ^ ''N| o , M 0 MS rju H  Me'N ^, ^ '' N | o, M 0 MS rju H

560  560
o OnsJ^'Vn^IPt T 1 if MeO^^N N^CI  o OnsJ ^ 'Vn ^ IPt T 1 if MeO ^^ N N ^ CI

561  561
's ^ } H N |? 0H N kMe F^^N^r\T''Cl H  's ^} H N |? 0H N kMe F ^^ N ^ r \ T''Cl H

562  562
MeT"l HN.9 1. A ,-, F' ^ N N Cl H  MeT "l HN.9 1. A, -, F '^ N N Cl H

[Tabla 481[Table 481

Rex  Rex
Sin Datos  No data

1  one
Rex299 ESI-: 402  Rex299 ESI-: 402

2  2
Rex298 ESI-: 420  Rex298 ESI-: 420

3  3
Rex292 RMN 'H (CDCI3): 1,11 (3H, s.a.), 1,21 (3H, s.a.), 2,17 (3H, s), 3,28 (2H, s.a.), 3,51 (2H, s.a.), 3,66 (2H, s.a.), 6,66-6,68 (2H, m), 7,03 (1H, dd, J = 0,8 Hz, 8,0 Hz).  Rex292 NMR 'H (CDCI3): 1.11 (3H, sa), 1.21 (3H, sa), 2.17 (3H, s), 3.28 (2H, sa), 3.51 (2H, sa), 3.66 (2H, sa), 6.66-6.68 (2H, m), 7.03 (1H, dd, J = 0.8 Hz, 8.0 Hz).

4  4
Rex4 EI: 236  Rex4 EI: 236

5  5
Rex299 ESI-: 388  Rex299 ESI-: 388

6  6
Rex298 ESI-: 406  Rex298 ESI-: 406

7  7
Rex292 RMN 1H (CDCI3): 1,50-1,65 (6H, m), 2,16 (3H, s), 3,36 (2H, s.a.), 3,71 (4H, m), 6,66-6,69 (2H, m), 7,02 (1H, d, J = 7,6 Hz).  Rex292 1H NMR (CDCI3): 1.50-1.65 (6H, m), 2.16 (3H, s), 3.36 (2H, sa), 3.71 (4H, m), 6.66 -6.69 (2H, m), 7.02 (1H, d, J = 7.6 Hz).

8  8
Rex4 EI: 248  Rex4 EI: 248

9  9
Rex299 RMN ‘H (DMSO-d6): 1,48-1,59 (6H, m), 2,30 (3H, s), 2,41 (3H, s), 3,33 (2H, s.a.), 3,54 (2H, s.a.), 7.02 (1H, dd, J = 1,2 Hz, 8,0 Hz),7,28 (1H, d, J = 8,0 Hz), 7,47 (1H, d, J = 4,0 Hz), 7,99 (1H, d, J = 1.2 Hz), 9,16 (1H, d, J = 4,4 Hz), 12,68 (1H, s), 12,84 (1H, s).  Rex299 NMR 'H (DMSO-d6): 1.48-1.59 (6H, m), 2.30 (3H, s), 2.41 (3H, s), 3.33 (2H, sa), 3.54 (2H, sa), 7.02 (1H, dd, J = 1.2 Hz, 8.0 Hz), 7.28 (1H, d, J = 8.0 Hz), 7.47 (1H, d, J = 4.0 Hz), 7.99 (1H, d, J = 1.2 Hz), 9.16 (1H, d, J = 4.4 Hz), 12.68 (1H, s), 12 , 84 (1H, s).

10  10
Rex298 ESI-: 418  Rex298 ESI-: 418

11  eleven
Rex292 RMN ’H (CDCI3): 1,24 (6H, d, J = 6,8 Hz), 2,19 (3H, s), 3,70 (2H, s.a.), 4,23-4,29 (1H, m), 5,85 (1H, s.a.), 6,97 (1H, dd, J = 1,6 Hz, 7,6 Hz), 7,06 (1H, d, J = 7,6 Hz), 7,13(1H, d, J = 1,6 Hz).  Rex292 NMR 'H (CDCI3): 1.24 (6H, d, J = 6.8 Hz), 2.19 (3H, s), 3.70 (2H, sa), 4.23-4.29 ( 1H, m), 5.85 (1H, sa), 6.97 (1H, dd, J = 1.6 Hz, 7.6 Hz), 7.06 (1H, d, J = 7.6 Hz) , 7.13 (1H, d, J = 1.6 Hz).

12  12
Rex4 RMN -|H (CDCI3): 1,29 (6H, d, J = 6,4 Hz), 2,65 (3H, s), 4,25-4,34 (1H, m), 5,99 (1H, s.a.), 7,42 (1H, d, J = 8,0 Hz), 7,94 (1H, dd, d = 2,0 Hz, 8,0 Hz), 8,30 (1H, d, J = 1,6 Hz).  Rex4 NMR - | H (CDCI3): 1.29 (6H, d, J = 6.4 Hz), 2.65 (3H, s), 4.25-4.34 (1H, m), 5.99 (1H, sa), 7.42 (1H, d, J = 8.0 Hz), 7.94 (1H, dd, d = 2.0 Hz, 8.0 Hz), 8.30 (1H, d , J = 1.6 Hz).

Rex  Rex
Sin Datos  No data

13  13
Rex299 RMN 'H (DMSO-d6): 1,14 (6H, d, J = 6,4 Hz), 2,31 (3H, s), 2,43 (3H, s), 4,06-4,11 (1H, m), 7,31 (1H, d, J = 8,0 Hz), 7,47 (1H, d, J = 4,4 Hz), 7,54 (1H, dd, J = 1,6 Hz, 8,0 Hz), 8,14 (1H, d, J = 7,6 Hz), 8,47 (1H, d, J = 1,6 Hz), 9,17 (1H, d, J = 4,4 Hz), 12,69 (1H, s), 12,84 (1H, s).  Rex299 NMR 'H (DMSO-d6): 1.14 (6H, d, J = 6.4 Hz), 2.31 (3H, s), 2.43 (3H, s), 4.06-4, 11 (1H, m), 7.31 (1H, d, J = 8.0 Hz), 7.47 (1H, d, J = 4.4 Hz), 7.54 (1H, dd, J = 1 , 6 Hz, 8.0 Hz), 8.14 (1H, d, J = 7.6 Hz), 8.47 (1H, d, J = 1.6 Hz), 9.17 (1H, d, J = 4.4 Hz), 12.69 (1H, s), 12.84 (1H, s).

14  14
Rex298 ESI-: 392  Rex298 ESI-: 392

15  fifteen
Rex299 RMN ‘H (DMSO-d6): 2,31 (3H, s), 2,44 (3H, s), 2,76 (3H, d, J = 4,4 Hz), 7,31 (1H, d, J = 8,0 Hz), 7,47 (1H, d, J = 4,4 Hz), 7,52 (1H, dd, J = 1,6 Hz, 8,0 Hz), 8,36 (1H, d, J = 4,8 Hz), 8,49 (1H, d, J = 1,6 Hz), 9,19 (1H, d, J = 4,4 Hz), 12,70 (1H, s), 12,85 (1H, s).  Rex299 NMR 'H (DMSO-d6): 2.31 (3H, s), 2.44 (3H, s), 2.76 (3H, d, J = 4.4 Hz), 7.31 (1H, d, J = 8.0 Hz), 7.47 (1H, d, J = 4.4 Hz), 7.52 (1H, dd, J = 1.6 Hz, 8.0 Hz), 8.36 (1H, d, J = 4.8 Hz), 8.49 (1H, d, J = 1.6 Hz), 9.19 (1H, d, J = 4.4 Hz), 12.70 (1H , s), 12.85 (1H, s).

16  16
Rex298 ESI-: 364  Rex298 ESI-: 364

17  17
Rex299 ESI-: 424  Rex299 ESI-: 424

18  18
Rex298 ESI-: 442  Rex298 ESI-: 442

19  19
Rex299 ESI-: 436  Rex299 ESI-: 436

20  twenty
Rex298 ESI-: 454  Rex298 ESI-: 454

21  twenty-one
Rex292 RMN ’H (CDCI3): 3,00 (3H, d, J = 4,9Hz), 3,94 (2H, m), 6,44 (1H, m), 6,58 (1H, dd, J = 2,4 Hz, 8,5 Hz), 6,64 (1H, d, J = 2,4 Hz), 7,67 (1H, d, J = 8,5 Hz).  Rex292 NMR 'H (CDCI3): 3.00 (3H, d, J = 4.9Hz), 3.94 (2H, m), 6.44 (1H, m), 6.58 (1H, dd, J = 2.4 Hz, 8.5 Hz), 6.64 (1H, d, J = 2.4 Hz), 7.67 (1H, d, J = 8.5 Hz).

22  22
Rex4 rMn -1H (CDCI3): 3,07 (3H, d, J = 4,9Hz), 6,15 (1H, m), 7,82 (1H, d, J = 8,3 Hz), 8,17 (1H, dd, J = 2,2 Hz, 8,3 Hz),8,29 (1H, d, J = 2,2 Hz).  Rex4 rMn -1H (CDCI3): 3.07 (3H, d, J = 4.9Hz), 6.15 (1H, m), 7.82 (1H, d, J = 8.3 Hz), 8, 17 (1H, dd, J = 2.2 Hz, 8.3 Hz), 8.29 (1H, d, J = 2.2 Hz).

23  2. 3
Rex299 ESI-: 366  Rex299 ESI-: 366

24  24
Rex298 ESI-: 384  Rex298 ESI-: 384

25  25
Rex292 RMN 1H (CDCI3): 1,05 (3H, t, J = 7,1 Hz), 1,24 (3H, t, J = 7,1 Hz), 3,18 (2H, q, J = 7,1 Hz), 3,35 (1H, m), 3,83 (3H, m), 6,56 (1H, dd, J = 2,2 Hz, 8,1 Hz), 6,67 (1H, d, J = 2,2 Hz), 7,03 (1H, d, J = 8,1 Hz).  Rex292 1H NMR (CDCI3): 1.05 (3H, t, J = 7.1 Hz), 1.24 (3H, t, J = 7.1 Hz), 3.18 (2H, q, J = 7 , 1 Hz), 3.35 (1H, m), 3.83 (3H, m), 6.56 (1H, dd, J = 2.2 Hz, 8.1 Hz), 6.67 (1H, d, J = 2.2 Hz), 7.03 (1H, d, J = 8.1 Hz).

[Tabla 501[Table 501

Rex  Rex
Sin Datos  No data

26  26
Rex4 RMN 1H (CDCI3): 1,09 (3H, t, J = 7,1 Hz), 1,29 (3H, t, J = 7,1 Hz), 3,06-3,21 (2H, m), 3,35-3,44 (1H, m), 3,76-3,85 (1H, m), 7,74 (1H, d, J = 8,3 Hz), 8,18 (1H, dd, J = 2,2 Hz, 8,3 Hz), 8,29 (1H, d, J = 2,2 Hz).  Rex4 1H NMR (CDCI3): 1.09 (3H, t, J = 7.1 Hz), 1.29 (3H, t, J = 7.1 Hz), 3.06-3.21 (2H, m ), 3.35-3.44 (1H, m), 3.76-3.85 (1H, m), 7.74 (1H, d, J = 8.3 Hz), 8.18 (1H, dd, J = 2.2 Hz, 8.3 Hz), 8.29 (1H, d, J = 2.2 Hz).

27  27
Rex299 ESI-: 408  Rex299 ESI-: 408

28  28
Rex298 ESI-: 426  Rex298 ESI-: 426

29  29
Rex292 RMN 1H (CDCI3): 1,08 (6H, d, J = 6,4 Hz), 2,21 (1H, s), 3,40-3,47 (1H, m), 4,21 (1H, d, J = 6,8 Hz), 7,14-7,18 (1H, m).  Rex292 1H NMR (CDCI3): 1.08 (6H, d, J = 6.4 Hz), 2.21 (1H, s), 3.40-3.47 (1H, m), 4.21 (1H , d, J = 6.8 Hz), 7.14-7.18 (1H, m).

30  30
Rex299 RMN 1H (DMSO-ds): 0,86-0,96(6H, m), 2,43 (1H, s), 3,15-3,20 (1H, m), 3,35 (3H, s), 7,43-7,70 (4H, m), 8,23 (1H, s), 9,18 (1H, s), 12,79 (1H, s), 13,06(1H, s).  Rex299 1H NMR (DMSO-ds): 0.86-0.96 (6H, m), 2.43 (1H, s), 3.15-3.20 (1H, m), 3.35 (3H, s), 7.43-7.70 (4H, m), 8.23 (1H, s), 9.18 (1H, s), 12.79 (1H, s), 13.06 (1H, s ).

31  31
Rex298 ESI-: 428  Rex298 ESI-: 428

32  32
Rex299 RMN 1H (DMSO-d6): 2,32-2,54 (9H, m), 7,33-7,70 (4H, m), 8,52 (1H, s), 9,18 (1H, s), 12,81 (1H, s), 13,09 (1H, s).  Rex299 1H NMR (DMSO-d6): 2.32-2.54 (9H, m), 7.33-7.70 (4H, m), 8.52 (1H, s), 9.18 (1H, s), 12.81 (1H, s), 13.09 (1H, s).

33  33
Rex298 ESI-: 400  Rex298 ESI-: 400

34  3. 4
Rex299 RMN 1H (DMSO-d6): 1,45-1,59 (6H, m), 2,54 (3H, s), 3,12 (2H, m), 3,56-3,63 (2H, m), 7,28-7,30 (1H, m), 7,38-7,41 (1H, m), 7,58-7,59 (1H, m), 7,99-7,99 (1H, m), 9,16-9,17 (1H, m), 12,85 (1H, s.a.), 13,13 (1H, s.a.).  Rex299 1H NMR (DMSO-d6): 1.45-1.59 (6H, m), 2.54 (3H, s), 3.12 (2H, m), 3.56-3.63 (2H, m), 7.28-7.30 (1H, m), 7.38-7.41 (1H, m), 7.58-7.59 (1H, m), 7.99-7.99 ( 1H, m), 9.16-9.17 (1H, m), 12.85 (1H, sa), 13.13 (1H, sa).

35  35
Rex298 ESI-: 438  Rex298 ESI-: 438

36  36
Rex292 RMN 1H (CDCI3): 1,25 (6H, d, J = 6,6 Hz), 3,94 (2H, m), 4,20-4,32 (1H, m), 6,22 (1H, m), 6,55-6,58 (1H, m), 6,63 (1H, d, J = 2,2 Hz), 7,61 (1H, dd, J = 1,2 Hz, 8,3 Hz).  Rex292 1H NMR (CDCI3): 1.25 (6H, d, J = 6.6 Hz), 3.94 (2H, m), 4.20-4.32 (1H, m), 6.22 (1H , m), 6.55-6.58 (1H, m), 6.63 (1H, d, J = 2.2 Hz), 7.61 (1H, dd, J = 1.2 Hz, 8, 3 Hz)

5 ______________________________________[Tabla 5115 ______________________________________ [Table 511

Rex  Rex
Sin Datos  No data

37  37
Rex4 RMN 1H (CDCI3): 1,30 (6H, d, J = 6,6 Hz), 4,28-4,36 (1H, m), 5,90 (1H, m), 7,78 (1H, d, J = 8,5 Hz), 8,16 (1H, dd, J = 2,2 Hz, 8,3 Hz), 8,28 (1H, d, J = 2,2 Hz).  Rex4 1H NMR (CDCI3): 1.30 (6H, d, J = 6.6 Hz), 4.28-4.36 (1H, m), 5.90 (1H, m), 7.78 (1H , d, J = 8.5 Hz), 8.16 (1H, dd, J = 2.2 Hz, 8.3 Hz), 8.28 (1H, d, J = 2.2 Hz).

38  38
Rex299 RMN 1H (DMSO-d6): 1,14 (6H, d, J = 6,6 Hz), 2,56 (3H, s), 4,01-4,02 (1H, m), 7,36-7,37 (2H, m), 7,58-7,59 (1H, m), 7,94-7,95 (1H, m), 8,24-8,26 (1H, m), 9,17 (1H, m), 12,85 (1H, s.a.), 13,14 (1H, s.a.).  Rex299 1H NMR (DMSO-d6): 1.14 (6H, d, J = 6.6 Hz), 2.56 (3H, s), 4.01-4.02 (1H, m), 7.36 -7.37 (2H, m), 7.58-7.59 (1H, m), 7.94-7.95 (1H, m), 8.24-8.26 (1H, m), 9 , 17 (1H, m), 12.85 (1H, sa), 13.14 (1H, sa).

39  39
Rex298 ESI-: 412  Rex298 ESI-: 412

40  40
Rex292 RMN 1H (CDCI3): 1,43-1,50 (2H, m), 1,57-1,63 (4H, m), 3,11-3,13 (4H, m), 3,84 (1H, s), 6,16-6,25 (2H, m), 7,62-7,66 (1H, m).  Rex292 1H NMR (CDCI3): 1.43-1.50 (2H, m), 1.57-1.63 (4H, m), 3.11-3.13 (4H, m), 3.84 ( 1H, s), 6.16-6.25 (2H, m), 7.62-7.66 (1H, m).

41  41
Rex41 RMN 1H (CDCI3): 1,54-1,63 (6H, m), 3,25 (4H, t, J = 5,6 Hz), 4,04 (1H, s), 7,83 (1H, d, J = 0,2 Hz), 7,88 (1H, dd, J = 0,2 Hz, 8,8 Hz), 8,07 (1H, d, J = 8,8 Hz).  Rex41 1 H NMR (CDCI3): 1.54-1.63 (6H, m), 3.25 (4H, t, J = 5.6 Hz), 4.04 (1H, s), 7.83 (1H , d, J = 0.2 Hz), 7.88 (1H, dd, J = 0.2 Hz, 8.8 Hz), 8.07 (1H, d, J = 8.8 Hz).

42  42
Rex299 ESI-: 452  Rex299 ESI-: 452

43  43
Rex298 RMN 1H (DMSO-d6): 1,44-1,50 (6H, m), 3,30-3,04 (4H, m), 3,10 (1H, s), 3,85 (1H, s), 7,46-7,48 (1H, m), 7,55-7,56 (1H, m), 7,64-7,66 (1H, m), 7,93 (1H, s.a.), 9,53 (1H, s.a.).  Rex298 1H NMR (DMSO-d6): 1.44-1.50 (6H, m), 3.30-3.04 (4H, m), 3.10 (1H, s), 3.85 (1H, s), 7.46-7.48 (1H, m), 7.55-7.56 (1H, m), 7.64-7.66 (1H, m), 7.93 (1H, sa) , 9.53 (1H, sa).

44  44
Rex292 rMn 1H (CdCi3): 1,09 (6H, t, J = 7,2 Hz), 2,28 (4H, q, J = 7,2 Hz), 3,84 (1H, s), 6,17-6,23 (2H, m), 7,67-7,71 (1 H, m).  Rex292 rMn 1H (CdCi3): 1.09 (6H, t, J = 7.2 Hz), 2.28 (4H, q, J = 7.2 Hz), 3.84 (1H, s), 6, 17-6.23 (2H, m), 7.67-7.71 (1 H, m).

45  Four. Five
Rex41 RMN 1H (CDCI3): 1,13 (6H, t, J = 7,2 Hz), 3,37 (4H, q, J = 7,2 Hz), 4,04 (3H, s), 7,82 (1H, d, J = 2,8 Hz), 7,87 (1H, dd, J = 2,8 Hz, 8,8 Hz), 8,12 (1H, d, J = 8,8 Hz).  Rex41 1 H NMR (CDCI3): 1.13 (6H, t, J = 7.2 Hz), 3.37 (4H, q, J = 7.2 Hz), 4.04 (3H, s), 7, 82 (1H, d, J = 2.8 Hz), 7.87 (1H, dd, J = 2.8 Hz, 8.8 Hz), 8.12 (1H, d, J = 8.8 Hz) .

Rex  Rex
Sin Datos  No data

46  46
Rex299 ESI-: 440  Rex299 ESI-: 440

47  47
Rex298 ESI-: 458  Rex298 ESI-: 458

[Tabla 52][Table 52]

Rex  Rex
Sin Datos  No data

48  48
Rex48 RMN 'H (CDCl3): 1,26 (6H, d, J = 6,4 Hz), 3,66 (2H, s.a.), 4,25-4,31 (1H, m), 6,57 (1H, s.a.), 6,696,73 (1H, m), 6,89 (1H, dd, J = 8,4 Hz, 11,6 Hz), 7,35 (1H, dd, J = 3,2 Hz, 6,8 Hz).  Rex48 NMR 'H (CDCl3): 1.26 (6H, d, J = 6.4 Hz), 3.66 (2H, sa), 4.25-4.31 (1H, m), 6.57 ( 1H, sa), 6,696.73 (1H, m), 6.89 (1H, dd, J = 8.4 Hz, 11.6 Hz), 7.35 (1H, dd, J = 3.2 Hz, 6.8 Hz).

49  49
Rex299 RMN ‘H (DMSO-d6): 1,14 (6H, d, J = 6,4 Hz), 2,39 (3H, s), 4,01-4,06 (1H, m), 7,24 (1H, t, J = 9,2 Hz), 7,49-7,53 (2H, m), 7,88 (1H, dd, J = 2,8 Hz, 6,4 Hz), 8,18 (1H, d, J = 8,0 Hz), 9,16 (1H, d, J = 4,4 Hz), 12,74 (1H, s), 12,96 (1H, s).  Rex299 NMR 'H (DMSO-d6): 1.14 (6H, d, J = 6.4 Hz), 2.39 (3H, s), 4.01-4.06 (1H, m), 7, 24 (1H, t, J = 9.2 Hz), 7.49-7.53 (2H, m), 7.88 (1H, dd, J = 2.8 Hz, 6.4 Hz), 8, 18 (1H, d, J = 8.0 Hz), 9.16 (1H, d, J = 4.4 Hz), 12.74 (1H, s), 12.96 (1H, s).

50  fifty
Rex298 RMN 1H (DMSO-d6): 1,14 (6H, d, J = 6,8 Hz), 2,41 (3H, S), 4,01-4,07 (1H, m), 7,24 (1H, t, J = 9,2 Hz), 7,62-7,66 (1H, m), 7,82-7,84 (1H, m), 7,87 (1H, s), 8,14 (1H, s), 8,15 (1H, m), 9,38 (1H, s).  Rex298 1H NMR (DMSO-d6): 1.14 (6H, d, J = 6.8 Hz), 2.41 (3H, S), 4.01-4.07 (1H, m), 7.24 (1H, t, J = 9.2 Hz), 7.62-7.66 (1H, m), 7.82-7.84 (1H, m), 7.87 (1H, s), 8, 14 (1H, s), 8.15 (1H, m), 9.38 (1H, s).

51  51
Rex48 rMn 1H (CDCI3): 1,50-1,65 (6H, m), 3,28 (2H, s.a.), 3,63 (2h, s.a.), 3,71 (2H, s.a.), 6,61-6,65 (2H, m), 6,86 (1H, t, J = 7,6 Hz).  Rex48 rMn 1H (CDCI3): 1.50-1.65 (6H, m), 3.28 (2H, sa), 3.63 (2h, sa), 3.71 (2H, sa), 6.61 -6.65 (2H, m), 6.86 (1H, t, J = 7.6 Hz).

52  52
Rex299 rMn -1H (DMSO-d6): 1,44-1,61 (6H, m), 2,45 (3H, s), 3,21 (2H, s.a.), 3,59 (2H, s.a.), 7,26 (1H, t, J = 8,8 Hz), 7,49-7,53 (2H, m), 7,63 (1 H, dd, J = 2,4 Hz, 6,4 Hz), 9,14 (1H, d, J = 4,4 Hz), 12,72 (1H, s), 12,89 (1H, s).  Rex299 rMn -1H (DMSO-d6): 1.44-1.61 (6H, m), 2.45 (3H, s), 3.21 (2H, sa), 3.59 (2H, sa), 7.26 (1H, t, J = 8.8 Hz), 7.49-7.53 (2H, m), 7.63 (1 H, dd, J = 2.4 Hz, 6.4 Hz) , 9.14 (1H, d, J = 4.4 Hz), 12.72 (1H, s), 12.89 (1H, s).

53  53
Rex298 RMN 1H (DMSO-d6): 1,45-1,62 (6H, m), 2,33 (3H, s), 3,22 (2H, m), 3,59 (2H, s.a.), 7,26 (1H, t, J = 8,8 Hz), 7,57-7,62 (2H, m), 7,86 (1H, s), 8,13 (1H, s), 9,35 (1H, s).  Rex298 1H NMR (DMSO-d6): 1.45-1.62 (6H, m), 2.33 (3H, s), 3.22 (2H, m), 3.59 (2H, sa), 7 , 26 (1H, t, J = 8.8 Hz), 7.57-7.62 (2H, m), 7.86 (1H, s), 8.13 (1H, s), 9.35 ( 1H, s).

54  54
Rex299 RMN 1H (DMSO-d6): 2,45 (3H, s), 3,26 (2H, s.a.), 3,53 (2H, t, J = 4,8 Hz), 3,63 (4H, s.a.), 7,28 (1H, t, J = 8,8 Hz), 7,51-7,57 (2H, m), 7,65 (1H, dd, J = 2,8 Hz, 6,0 Hz), 9,14 (1H, d, J = 4,4 Hz), 12,73 (1H, s), 12,89 (1H, s).  Rex299 1H NMR (DMSO-d6): 2.45 (3H, s), 3.26 (2H, sa), 3.53 (2H, t, J = 4.8 Hz), 3.63 (4H, sa ), 7.28 (1H, t, J = 8.8 Hz), 7.51-7.57 (2H, m), 7.65 (1H, dd, J = 2.8 Hz, 6.0 Hz ), 9.14 (1H, d, J = 4.4 Hz), 12.73 (1H, s), 12.89 (1H, s).

5 ______________________________________[Tabla 53]5 ______________________________________ [Table 53]

Rex  Rex
Sin Datos  No data

55  55
Rex298 RMN 1H (DMSO-d6): 2,41 (3H, s), 3,27 (2H, m), 3,54 (2H, t, J = 4,8H), 3,64 (4H, s.a.), 7,28 (1H, t, J = 8,8 Hz), 7,61-7,64 (2H, m), 7,88 (1H, s.a.), 8,14 (1H, s.a.), 9,38 (1H, s).  Rex298 1H NMR (DMSO-d6): 2.41 (3H, s), 3.27 (2H, m), 3.54 (2H, t, J = 4.8H), 3.64 (4H, sa) , 7.28 (1H, t, J = 8.8 Hz), 7.61-7.64 (2H, m), 7.88 (1H, sa), 8.14 (1H, sa), 9, 38 (1H, s).

56  56
Rex292 RMN 'H (CDC3): 1,08 (3H, t, J = 7,2 Hz), 1,23 (3H, t, J = 7,2 Hz), 3,24 (2H, q, J = 7,2 Hz), 3,55 (2H, m), 3,70 (2H, s.a.), 6,56 (1H, dd, J = 3,2 Hz, 5,6 Hz), 6,62 (1H, m), 6,85 (1H, t, J = 8,8 Hz).  Rex292 NMR 'H (CDC3): 1.08 (3H, t, J = 7.2 Hz), 1.23 (3H, t, J = 7.2 Hz), 3.24 (2H, q, J = 7.2 Hz), 3.55 (2H, m), 3.70 (2H, sa), 6.56 (1H, dd, J = 3.2 Hz, 5.6 Hz), 6.62 (1H , m), 6.85 (1H, t, J = 8.8 Hz).

57  57
Rex299 rMn -1H (DMSO-d6): 1,01 (3H, t, J = 7,2 Hz), 1,13 (3H, t, J = 7,2 Hz), 2,45 (3H, s), 3,17 (2H, q, J = 7,2 Hz), 3,44 (2H, m), 7,26 (1 H, t, J = 8,8 Hz), 7,46 (1H, m), 7,52 (1H, d, J = 4,4 Hz), 7,67 (1H, dd, J = 2,8 Hz, 6,0 Hz), 9,15 (1H, d, J = 4,4 Hz), 12,73 (1H, s), 12,94 (1H, s).  Rex299 rMn -1H (DMSO-d6): 1.01 (3H, t, J = 7.2 Hz), 1.13 (3H, t, J = 7.2 Hz), 2.45 (3H, s) , 3.17 (2H, q, J = 7.2 Hz), 3.44 (2H, m), 7.26 (1 H, t, J = 8.8 Hz), 7.46 (1H, m ), 7.52 (1H, d, J = 4.4 Hz), 7.67 (1H, dd, J = 2.8 Hz, 6.0 Hz), 9.15 (1H, d, J = 4 , 4 Hz), 12.73 (1H, s), 12.94 (1H, s).

58  58
Rex298 RMN 1H (DMSO-d6): 1,02 (3H, t, J = 7,2 Hz), 1,13 (3H, t, J = 7,2 Hz), 2,40 (3H, s), 3,18 (2H, q, J = 7,2 Hz), 3,45 (2H, q, J = 7,2 Hz), 7,27 (1H, t, J = 9,2 Hz), 7,58-7,61 (2H, m), 7,87 (1H, s.a.), 8,14 (1H, s.a.), 9,35 (1H, s).  Rex298 1 H NMR (DMSO-d6): 1.02 (3H, t, J = 7.2 Hz), 1.13 (3H, t, J = 7.2 Hz), 2.40 (3H, s), 3.18 (2H, q, J = 7.2 Hz), 3.45 (2H, q, J = 7.2 Hz), 7.27 (1H, t, J = 9.2 Hz), 7, 58-7.61 (2H, m), 7.87 (1H, sa), 8.14 (1H, sa), 9.35 (1H, s).

59  59
Rex292 RMN 1H (CDCI3): 1,05 (6H, d, J = 6,4 Hz), 3,27-3,49 (1H, m), 3,90 (1H, s), 4,55 (1H, d, J = 6,4 Hz), 6,62-6,28 (2H, m), 7,65-7,69 (1H, m).  Rex292 1H NMR (CDCI3): 1.05 (6H, d, J = 6.4 Hz), 3.27-3.49 (1H, m), 3.90 (1H, s), 4.55 (1H , d, J = 6.4 Hz), 6.62-6.28 (2H, m), 7.65-7.69 (1H, m).

60  60
Rex41 RMN 1H (CDCI3): 1,08 (6H, t, J = 6,8 Hz), 3,48 (1H, q, J = 7,6 Hz), 4,11 (1H, s), 4,75 (1H, d, J = 7,6 Hz), 7,88 (1H, d, J = 2,0 Hz), 7,94 (1H, dd, J = 2,0 Hz, 8,4 Hz), 8,12 (1H, d, J = 8,4 Hz).  Rex41 1 H NMR (CDCI3): 1.08 (6H, t, J = 6.8 Hz), 3.48 (1H, q, J = 7.6 Hz), 4.11 (1H, s), 4, 75 (1H, d, J = 7.6 Hz), 7.88 (1H, d, J = 2.0 Hz), 7.94 (1H, dd, J = 2.0 Hz, 8.4 Hz) , 8.12 (1H, d, J = 8.4 Hz).

61  61
Rex299 rMn -1H (DMSO-d6): 0,94-0,99 (6H, m), 3,18-3,24 (1H, m), 2,49 (1H, s), 3,92 (1H, s), 7,06-7,08 (1H, m), 7,20-7,23 (1H, m), 7,39-7,40 (1H, m), 7,61-7,69 (2H, m), 9,20 (1H, s.a.), 12,88 (1H, s.a.), 13,28 (1H, s.a.).  Rex299 rMn -1H (DMSO-d6): 0.94-0.99 (6H, m), 3.18-3.24 (1H, m), 2.49 (1H, s), 3.92 (1H , s), 7.06-7.08 (1H, m), 7.20-7.23 (1H, m), 7.39-7.40 (1H, m), 7.61-7.69 (2H, m), 9.20 (1H, sa), 12.88 (1H, sa), 13.28 (1H, sa).

[Tabla 54][Table 54]

Rex  Rex
Sin Datos  No data

62  62
Rex298 ESI-: 444  Rex298 ESI-: 444

63  63
Rex292 RMN 1H (CDCI3): 1,40-1,46 (2H, m), 1,62-1,67 (4H, m), 2,96-2,99 (4H, m), 3,97 (1H, s.a.), 7,06-7,10 (2H, m), 7,15-7,18 (1H, m).  Rex292 1H NMR (CDCI3): 1.40-1.46 (2H, m), 1.62-1.67 (4H, m), 2.96-2.99 (4H, m), 3.97 ( 1H, sa), 7.06-7.10 (2H, m), 7.15-7.18 (1H, m).

64  64
Rex41 RMN 1H (CDCI3): 1,45-1,71 (7H, m), 3,06 (4H, t, J = 5,6 Hz), 7,46-7,52 (1H, m), 8,00-8,04 (1H, m), 8,43-8,46 (1H, m).  Rex41 1 H NMR (CDCI3): 1.45-1.71 (7H, m), 3.06 (4H, t, J = 5.6 Hz), 7.46-7.52 (1H, m), 8 , 00-8.04 (1H, m), 8.43-8.46 (1H, m).

65  65
Rex299 ESI-: 440  Rex299 ESI-: 440

66  66
Rex298 RMN 1H (DMSO-d6): 1,31-1,38 (4H, m), 1,51-1,55 (7H, m), 2,44 (1H, s), 2,83-2,92 (7H, m), 7,56-7,58 (2H, m), 8,14-8,26 (3H, m), 9,77 (1H, s.a.).  Rex298 1H NMR (DMSO-d6): 1.31-1.38 (4H, m), 1.51-1.55 (7H, m), 2.44 (1H, s), 2.83-2, 92 (7H, m), 7.56-7.58 (2H, m), 8.14-8.26 (3H, m), 9.77 (1H, sa).

67  67
Rex292 RMN 1H (CDCI3): 1,43-1,45 (2H, m), 1,64 (4H, m), 2,22 (1H, s), 3,21 (2H, m), 3,66-3,76 (4H, m), 6,486,51 (2H, m), 6,94 (1H, d, J = 8,0 Hz).  Rex292 1H NMR (CDCI3): 1.43-1.45 (2H, m), 1.64 (4H, m), 2.22 (1H, s), 3.21 (2H, m), 3.66 -3.76 (4H, m), 6.486.51 (2H, m), 6.94 (1H, d, J = 8.0 Hz).

68  68
Rex4 RMN 1H (CDCI3): 1,43-1,87 (6H, m), 2,42 (3H, s), 3,13-3,15 (2H, m), 3,69-3,83 (2H, m), 7,32 (1H, d, J = 8,4 Hz), 8,07-8,11 (2H, m).  Rex4 1H NMR (CDCI3): 1.43-1.87 (6H, m), 2.42 (3H, s), 3.13-3.15 (2H, m), 3.69-3.83 ( 2H, m), 7.32 (1H, d, J = 8.4 Hz), 8.07-8.11 (2H, m).

69  69
Rex299 ESI-: 400  Rex299 ESI-: 400

70  70
Rex298 ESI-: 418  Rex298 ESI-: 418

71  71
Rex292 RMN 1H (CD3OD): 2,23 (3H, s), 2,84 (3H, s), 6,50-6,55 (2H, m), 7,14 (1H, d, J = 8,4 Hz).  Rex292 1H NMR (CD3OD): 2.23 (3H, s), 2.84 (3H, s), 6.50-6.55 (2H, m), 7.14 (1H, d, J = 8, 4 Hz)

72  72
Rex4 RMN 1H (CDCI3): 2,54 (3H, s), 3,04 (3H, d, J = 4,8 Hz), 5,80 (1H, s.a.), 7,49 (1H, d, J = 8,4 Hz), 8,048,12 (1H,m).  Rex4 1H NMR (CDCI3): 2.54 (3H, s), 3.04 (3H, d, J = 4.8 Hz), 5.80 (1H, sa), 7.49 (1H, d, J = 8.4 Hz), 8.048.12 (1H, m).

Rex  Rex
Sin Datos  No data

73  73
Rex299 ESI-: 346  Rex299 ESI-: 346

74  74
Rex298 ESI-: 364  Rex298 ESI-: 364

75  75
Rex292 RMN 'H (CDCl3): 1,54-1,62 (6H, m), 3,20-3,23 (2H, m), 3,62-3,64 (1H, m), 3,77 (5H, m), 6,20 (1H, d, J = 2,0 Hz), 6,27 (1H, dd, J = 2,0 Hz, 8,1 Hz), 7,02 (1H, d, J = 8,1 Hz).  Rex292 NMR 'H (CDCl3): 1.54-1.62 (6H, m), 3.20-3.23 (2H, m), 3.62-3.64 (1H, m), 3.77 (5H, m), 6.20 (1H, d, J = 2.0 Hz), 6.27 (1H, dd, J = 2.0 Hz, 8.1 Hz), 7.02 (1H, d , J = 8.1 Hz).

76  76
Rex299 ESI-: 416  Rex299 ESI-: 416

[Tabla 551[Table 551

Rex  Rex
Sin Datos  No data

77  77
Rex298 ESI-: 434  Rex298 ESI-: 434

78  78
Rex292 RMN 1H (CDCI3): 1,45-1,47 (2H, m), 1,65 (4H, m), 2,17 (3H, s), 3,18-3,21 (2H, m), 3,59-3,66 (3H, m), 3,78-3,82 (1H, m), 6,49 (1H, d, J = 2,7 Hz), 6,60 (1H, dd, J = 2,7 Hz, 8,3 Hz), 6,97 (1H, d, J = 8,3 Hz).  Rex292 1H NMR (CDCI3): 1.45-1.47 (2H, m), 1.65 (4H, m), 2.17 (3H, s), 3.18-3.21 (2H, m) , 3.59-3.66 (3H, m), 3.78-3.82 (1H, m), 6.49 (1H, d, J = 2.7 Hz), 6.60 (1H, dd , J = 2.7 Hz, 8.3 Hz), 6.97 (1H, d, J = 8.3 Hz).

79  79
Rex4 RMN 1H (CDCI3): 1,48-1,54 (2H, m), 1,70 (4H, m), 2,42 (3H, s), 3,16-3,20 (2h, m),' 3,73-3,80 (2H, m), 7,39 (1H, d, J = 8,5 Hz), 8,05 (1H, d, J = 2,2 Hz), 8,12 (1H, dd, J = 2,2 Hz, 8,5 Hz).  Rex4 1H NMR (CDCI3): 1.48-1.54 (2H, m), 1.70 (4H, m), 2.42 (3H, s), 3.16-3.20 (2h, m) , '3.73-3.80 (2H, m), 7.39 (1H, d, J = 8.5 Hz), 8.05 (1H, d, J = 2.2 Hz), 8.12 (1H, dd, J = 2.2 Hz, 8.5 Hz).

80  80
Rex299 ESI-: 400  Rex299 ESI-: 400

81  81
Rex298 ESI-: 418  Rex298 ESI-: 418

82  82
Rex292 RMN 1H (CDCI3): 2,31 (3H, s), 2,98 (3H, d, J = 4,9Hz), 3,60 (2H, m), 5,69 (1H, m), 6,64 (1H, dd, J = 2,7 Hz, 8,1 Hz), 6,70 (1H, d, J = 2,7 Hz), 6,98 (1H, d, J = 8,1 Hz).  Rex292 1H NMR (CDCI3): 2.31 (3H, s), 2.98 (3H, d, J = 4.9Hz), 3.60 (2H, m), 5.69 (1H, m), 6 , 64 (1H, dd, J = 2.7 Hz, 8.1 Hz), 6.70 (1H, d, J = 2.7 Hz), 6.98 (1H, d, J = 8.1 Hz ).

83  83
Rex299 ESI-: 346  Rex299 ESI-: 346

84  84
Rex298 ESI-: 364  Rex298 ESI-: 364

85  85
Rex48 RMN 1H (CDCI3): 2,97 (3H, d, J = 4,8 Hz), 4,03 (2H, s.a.), 5,76 (1H, s.a.), 6,77 (1H, dd, J = 2,4 Hz, 8,0 Hz), 6,90 (1H, d, J = 2,4 Hz), 7,33 (1H, d, J = 8,0 Hz).  Rex48 1H NMR (CDCI3): 2.97 (3H, d, J = 4.8 Hz), 4.03 (2H, sa), 5.76 (1H, sa), 6.77 (1H, dd, J = 2.4 Hz, 8.0 Hz), 6.90 (1H, d, J = 2.4 Hz), 7.33 (1H, d, J = 8.0 Hz).

86  86
Rex299 RMN 'H (DMSo-d6): 2,51 (3H, s), 2,73 (3H, d, J = 4,4 Hz), 7,48 (1H, d, J = 8,4 Hz), 7,63-7,65 (2H, m), 8,22 (1H, d, J = 1,6 Hz), 8,38 (1H, d, J = 4,8 Hz), 9,18 (1H, d, J = 4,4 Hz), 12,89 (1H, s), 13,27 (1H, s).  Rex299 NMR 'H (DMSo-d6): 2.51 (3H, s), 2.73 (3H, d, J = 4.4 Hz), 7.48 (1H, d, J = 8.4 Hz) , 7.63-7.65 (2H, m), 8.22 (1H, d, J = 1.6 Hz), 8.38 (1H, d, J = 4.8 Hz), 9.18 ( 1H, d, J = 4.4 Hz), 12.89 (1H, s), 13.27 (1H, s).

87  87
Rex298 RMN 1H (DMSO-d6): 2,45 (3H, s), 2,73 (3H, d, J = 4,8 Hz), 7,48 (1H, d, J = 8,4 Hz), 7,88 (1H, d, J = 8,8 Hz), 7,89 (1H, s), 8,12 (1H, d, J = 2,0 Hz), 8,17 (1H, s), 8,38 (1H, m), 9,62 (1H, s).  Rex298 1H NMR (DMSO-d6): 2.45 (3H, s), 2.73 (3H, d, J = 4.8 Hz), 7.48 (1H, d, J = 8.4 Hz), 7.88 (1H, d, J = 8.8 Hz), 7.89 (1H, s), 8.12 (1H, d, J = 2.0 Hz), 8.17 (1H, s), 8.38 (1H, m), 9.62 (1H, s).

5 ______________________________________[Tabla 5615 ______________________________________ [Table 561

Rex  Rex
Sin Datos  No data

88  88
Rex48 RMN 1H (CDCI3): 3,01 (3H, dd, J = 1,2 Hz, 5,2 Hz), 3,69 (2H, s.a.), 6,70-6,74 (1H, m), 6,77 (1H, s.a.), 6,90 (1H, dd, J = 8,4 Hz, 11,6 Hz), 7,38 (1H, dd, J = 3,2 Hz, 6,4 Hz).  Rex48 1H NMR (CDCI3): 3.01 (3H, dd, J = 1.2 Hz, 5.2 Hz), 3.69 (2H, sa), 6.70-6.74 (1H, m), 6.77 (1H, sa), 6.90 (1H, dd, J = 8.4 Hz, 11.6 Hz), 7.38 (1H, dd, J = 3.2 Hz, 6.4 Hz) .

89  89
Rex299 RMN !H (DMSO-d6): 2,49 (3H, s), 2,77 (3H, d, J = 4,4 Hz), 7,26 (1H, t, J = 8,8 Hz), 7,53-7,58 (2H, m), 7,95 (1H, dd, J = 2,8 Hz, 6,4 Hz), 8,24 (1H, s.a.), 9,16 (1H, d, J = 4,4 Hz), 12,75 (1H, s), 12,96 (1H, s).  Rex299 NMR! H (DMSO-d6): 2.49 (3H, s), 2.77 (3H, d, J = 4.4 Hz), 7.26 (1H, t, J = 8.8 Hz) , 7.53-7.58 (2H, m), 7.95 (1H, dd, J = 2.8 Hz, 6.4 Hz), 8.24 (1H, sa), 9.16 (1H, d, J = 4.4 Hz), 12.75 (1H, s), 12.96 (1H, s).

90  90
Rex298 RMN 1H (DMSO-d6): 2,40 (3H, s), 2,77 (3H, d, J = 4,8 Hz), 7,26 (1H, t, J = 10,0 Hz), 7,64-7,68 (1H, m), 7,87 (1H, s.a.), 7,92 (1H, dd, J = 2,4 Hz, 6,4 Hz), 8,14 (1H, s.a.), 8,21 (1H, s.a.), 9,39 (1H, s.a.).  Rex298 1H NMR (DMSO-d6): 2.40 (3H, s), 2.77 (3H, d, J = 4.8 Hz), 7.26 (1H, t, J = 10.0 Hz), 7.64-7.68 (1H, m), 7.87 (1H, sa), 7.92 (1H, dd, J = 2.4 Hz, 6.4 Hz), 8.14 (1H, sa ), 8.21 (1H, sa), 9.39 (1H, sa).

91  91
Rex292 rMn 1H (CDCI3): 2,55 (3H, s), 3,91 (3H, s), 6,22-6,30 (2H,' m), 7,65-7,69 (1H, m).  Rex292 rMn 1H (CDCI3): 2.55 (3H, s), 3.91 (3H, s), 6.22-6.30 (2H, 'm), 7.65-7.69 (1H, m ).

92  92
Rex41 RMN 1H (CDCI3): 2,66 (3H, d, J = 5,2 Hz), 4,11 (3H, s), 4,84 (1H, d, J = 5,2 Hz), 7,89 (1H, d, J = 2,0 Hz), 7,94 (1H, dd, J = 2,0 Hz, 8,8 Hz), 8,12 (1H, d, J = 8,8 Hz).  Rex41 1 H NMR (CDCI3): 2.66 (3H, d, J = 5.2 Hz), 4.11 (3H, s), 4.84 (1H, d, J = 5.2 Hz), 7, 89 (1H, d, J = 2.0 Hz), 7.94 (1H, dd, J = 2.0 Hz, 8.8 Hz), 8.12 (1H, d, J = 8.8 Hz) .

93  93
Rex299 ESI-: 398  Rex299 ESI-: 398

94  94
Rex298 ESI-: 416  Rex298 ESI-: 416

95  95
Rex292 RMN 1H (CDCI3): 2,97 (3H, d, J = 4,6 Hz), 3,90 (3H, s), 3,96 (2H, m), 6,20 (1H, d, J = 2,2 Hz), 6,34 (1H, dd, J = 2,2 Hz, 8,5 Hz), 7,66 (1 H, m), 8,04 (1H, d, J = 8,5 Hz).  Rex292 1H NMR (CDCI3): 2.97 (3H, d, J = 4.6 Hz), 3.90 (3H, s), 3.96 (2H, m), 6.20 (1H, d, J = 2.2 Hz), 6.34 (1H, dd, J = 2.2 Hz, 8.5 Hz), 7.66 (1 H, m), 8.04 (1H, d, J = 8, 5 Hz)

96  96
Rex4 RMN 1H (CDCI3): 3,04 (3H, d, J = 4,9Hz), 4,09 (3H, s), 7,74 (1H, m), 7,84 (1H, d, J = 2,2 Hz), 7,93 (1H, dd, J = 2,2 Hz, 8,5 Hz), 8,39 (1H, d, J = 8,5 Hz).  Rex4 1H NMR (CDCI3): 3.04 (3H, d, J = 4.9Hz), 4.09 (3H, s), 7.74 (1H, m), 7.84 (1H, d, J = 2.2 Hz), 7.93 (1H, dd, J = 2.2 Hz, 8.5 Hz), 8.39 (1H, d, J = 8.5 Hz).

97  97
Rex299 ESI-: 362  Rex299 ESI-: 362

[Tabla 571[Table 571

Rex  Rex
Sin Datos  No data

98  98
Rex298 ESI-: 380  Rex298 ESI-: 380

99  99
Rex48 RMN 1H (CDCI3): 0,83-0,88 (1H, m), 1,42-1,65 (5H, m), 3,15 (2H, dd, J = 9,2 Hz, 15,2 Hz), 3,64-3,76 (2H, m), 4,01 (2H, s.a.), 6,78 (1H, dd, J = 2,4 Hz, 8,4 Hz), 6,90 (1H, d, J = 2,8 Hz), 7,05 (1H, d, J = 8,4 Hz).  Rex48 1H NMR (CDCI3): 0.83-0.88 (1H, m), 1.42-1.65 (5H, m), 3.15 (2H, dd, J = 9.2 Hz, 15, 2 Hz), 3.64-3.76 (2H, m), 4.01 (2H, sa), 6.78 (1H, dd, J = 2.4 Hz, 8.4 Hz), 6.90 (1H, d, J = 2.8 Hz), 7.05 (1H, d, J = 8.4 Hz).

100  100
Rex299 RMN 1H (DMSO-d6): 1,37-1,59 (6H, m), 2,54 (3H, s), 3,06-3,11 (2H, m), 3,51-3,62 (2H, m), 7,40 (1H, d, J = 8,4 Hz), 7,61-7,66 (2H, m), 8,27 (1H, d, J = 2,0 Hz), 9,18 (1H, d, J = 4,0 Hz), 12,89 (1H, s), 13,28 (1H, s).  Rex299 1H NMR (DMSO-d6): 1.37-1.59 (6H, m), 2.54 (3H, s), 3.06-3.11 (2H, m), 3.51-3, 62 (2H, m), 7.40 (1H, d, J = 8.4 Hz), 7.61-7.66 (2H, m), 8.27 (1H, d, J = 2.0 Hz ), 9.18 (1H, d, J = 4.0 Hz), 12.89 (1H, s), 13.28 (1H, s).

101  101
Rex298 RMN 1H (DMSO-d6): 1,37-1,59 (6H, m), 2,45 (3H, s), 3,06-3,11 (2H, m), 3,52-3,62 (2H, m), 7,40 (1H, d, J = 8,0 Hz), 7,90 (1H, s.a.), 7,92 (1H, m), 8,16 (1H, s.a.), 8,19 (1H, d, J = 2,0 Hz), 9,62 (1H, s).  Rex298 1H NMR (DMSO-d6): 1.37-1.59 (6H, m), 2.45 (3H, s), 3.06-3.11 (2H, m), 3.52-3, 62 (2H, m), 7.40 (1H, d, J = 8.0 Hz), 7.90 (1H, sa), 7.92 (1H, m), 8.16 (1H, sa), 8.19 (1H, d, J = 2.0 Hz), 9.62 (1H, s).

102  102
Rex353 ESI-: 346  Rex353 ESI-: 346

103  103
Rex353 ESI-: 454  Rex353 ESI-: 454

104  104
Rex353 ESI-: 346  Rex353 ESI-: 346

105  105
Rex353 ESI-: 346  Rex353 ESI-: 346

Rex  Rex
Sin Datos  No data

106  106
Rex299 RMN 'H (DMSO-d6): 2,53 (3H, s), 2,72 (3H, d, J = 4,4 Hz), 7,41 (1H, d, J = 8,8 Hz), 7,48-7,56 (2H, m), 8,36 (1H, d, J = 4,6 Hz), 9,16 (1H, d, J = 3,7 Hz), 12,80 (1H, s), 13,10 (1H, s).  Rex299 NMR 'H (DMSO-d6): 2.53 (3H, s), 2.72 (3H, d, J = 4.4 Hz), 7.41 (1H, d, J = 8.8 Hz) , 7.48-7.56 (2H, m), 8.36 (1H, d, J = 4.6 Hz), 9.16 (1H, d, J = 3.7 Hz), 12.80 ( 1H, s), 13.10 (1H, s).

107  107
Rex298 RMN 1H (DMSO-d6): 2,43 (3H, 2,7 Hz, 8,8 Hz), 7,77 (1H, d, J (1H, s).___________________ s), 2,73 (3H, d, J = 4,6 Hz), 7,41 (1H, d, J = 8,5 Hz), 7,65 (1H, dd, J = = 2,4 Hz), 7,88 (1H, s), 8,14 (1H, s), 8,35 (1 H, d, J = 4,6 Hz), 9,43  Rex298 1H NMR (DMSO-d6): 2.43 (3H, 2.7 Hz, 8.8 Hz), 7.77 (1H, d, J (1H, s) .___________________ s), 2.73 (3H , d, J = 4.6 Hz), 7.41 (1H, d, J = 8.5 Hz), 7.65 (1H, dd, J = = 2.4 Hz), 7.88 (1H, s), 8.14 (1H, s), 8.35 (1 H, d, J = 4.6 Hz), 9.43

[Tabla 581[Table 581

Rex  Rex
Sin Datos  No data

108  108
Rex353 RMN 1H (CDCl3): 1,29 (3H, t, J = 7,6 Hz), 2,87 (2H, q, J = 7,3 Hz), 3,04 (3H, s), 5,56 (1H, s.a.), 6,25 (1H, s.a.), 7,34 (1H, d, J = 8,8 Hz), 7,74 (1H, a-), 7,81 (1H, dd, J = 2,9Hz, 8,8 Hz), 7,93 (1H, d, J = 2,7 Hz), 10,95 (1H, s.a.).  Rex353 1H NMR (CDCl3): 1.29 (3H, t, J = 7.6 Hz), 2.87 (2H, q, J = 7.3 Hz), 3.04 (3H, s), 5, 56 (1H, sa), 6.25 (1H, sa), 7.34 (1H, d, J = 8.8 Hz), 7.74 (1H, a-), 7.81 (1H, dd, J = 2.9Hz, 8.8Hz), 7.93 (1H, d, J = 2.7Hz), 10.95 (1H, sa).

109  109
Rex353 RMN 1H (CDCI3): 1,31 (3H, t, J = 7,6 Hz), 2,89 (2H, q, J = 7,3 Hz), 3,03 (3H, d, J = 4,9Hz), 4,04 (3H, s), 5,53 (1H, s.a.), 6,12 (1H, s.a.), 7,28 (1H, m), 7,49 (1H, s), 7,74 (1H, s.a.), 8,58 (1H, d, J = 8,3 Hz), 11,43 (1H, s.a.).  Rex353 1 H NMR (CDCI3): 1.31 (3H, t, J = 7.6 Hz), 2.89 (2H, q, J = 7.3 Hz), 3.03 (3H, d, J = 4 , 9Hz), 4.04 (3H, s), 5.53 (1H, sa), 6.12 (1H, sa), 7.28 (1H, m), 7.49 (1H, s), 7 , 74 (1H, sa), 8.58 (1H, d, J = 8.3 Hz), 11.43 (1H, sa).

110  110
Rex292 RMN lH (CDCI3): 2,18 (3H, s), 2,98 (3H, d, J = 4,9Hz), 3,88 (2H, m), 5,97 (1H, m), 6,64 (1H, d, J = 8,1 Hz), 7,44 (1H, dd, J = 2,0 Hz, 8,3 Hz), 7,51 (1H, m).  Rex292 1 H NMR (CDCI3): 2.18 (3H, s), 2.98 (3H, d, J = 4.9Hz), 3.88 (2H, m), 5.97 (1H, m), 6 , 64 (1H, d, J = 8.1 Hz), 7.44 (1H, dd, J = 2.0 Hz, 8.3 Hz), 7.51 (1H, m).

111  111
Rex4 RMN 'H (CdC|3): 2,64(3H, s), 3,05 (3H, d, J = 4,9H), 6,17 (1H, m), 7,67 (1H, dd, J = 2,0 Hz, 8,3 Hz), 7,76 (1H, d, J = 2,0 Hz), 8,00 (1H, d, J = 8,3 Hz).  Rex4 NMR 'H (CdC | 3): 2.64 (3H, s), 3.05 (3H, d, J = 4.9H), 6.17 (1H, m), 7.67 (1H, dd , J = 2.0 Hz, 8.3 Hz), 7.76 (1H, d, J = 2.0 Hz), 8.00 (1H, d, J = 8.3 Hz).

112  112
Rex353 ESI-: 346  Rex353 ESI-: 346

113  113
Rex353 ESI-: 400  Rex353 ESI-: 400

114  114
Rex292 RMN lH (CDCI3): 2,21 (3H, s), 2,99 (3H, d, J = 4,9Hz), 3,70 (2H, m), 5,72 (1H, m), 6,71-6,77 (2H, m), 7,00-7,04 (1H, m).  Rex292 NMR lH (CDCI3): 2.21 (3H, s), 2.99 (3H, d, J = 4.9Hz), 3.70 (2H, m), 5.72 (1H, m), 6 , 71-6.77 (2H, m), 7.00-7.04 (1H, m).

115  115
Rex353 RMN lH (CDCI3): 1,30 (3H, t, J = 7,3 Hz), 2,42 (3H, s), 2,87 (2H, q, J = 7,3 Hz), 3,02 (3H, d, J = 4,9Hz), 5,50 (1H, m), 5,75 (1H, m), 7,09-7,11 (1H, m), 7,75 (1H, m), 8,16-8,18 (1H, m), 10,74 (1H, m).  Rex353 NMR lH (CDCI3): 1.30 (3H, t, J = 7.3 Hz), 2.42 (3H, s), 2.87 (2H, q, J = 7.3 Hz), 3, 02 (3H, d, J = 4.9Hz), 5.50 (1H, m), 5.75 (1H, m), 7.09-7.11 (1H, m), 7.75 (1H, m), 8.16-8.18 (1H, m), 10.74 (1H, m).

116  116
Rex353 ESI-: 366  Rex353 ESI-: 366

117  117
Rex353 ESI-: 325  Rex353 ESI-: 325

5 ______________________________________[Tabla 5915 ______________________________________ [Table 591

Rex  Rex
Sin Datos  No data

118  118
Rex292 RMN lH (CDCI3): 2,98 (3H, d, J = 4,9Hz), 3,85 (2H, s.a.), 6,06 (1H, s.a.), 6,98-7,01 (2H, m), 7,25-7,29 (1H, m).  Rex292 1 H NMR (CDCI3): 2.98 (3H, d, J = 4.9Hz), 3.85 (2H, sa), 6.06 (1H, sa), 6.98-7.01 (2H, m), 7.25-7.29 (1H, m).

119  119
Rex353 RMN lH (CDCI3): 1,31 (3H, t, J = 7,6 Hz), 2,92 (2H, q, J = 7,3 Hz), 3,05 (3H, d, J = 4,9Hz), 5,57 (1H, s.a.), 6,13 (1H, s.a.), 7,18 (1H, m), 7,52 (1H, m), 7,73 (1H, s), 8,87 (1H, d, J = 8,5 Hz), 11,15 (1H, s.a.).  Rex353 NMR lH (CDCI3): 1.31 (3H, t, J = 7.6 Hz), 2.92 (2H, q, J = 7.3 Hz), 3.05 (3H, d, J = 4 , 9Hz), 5.57 (1H, sa), 6.13 (1H, sa), 7.18 (1H, m), 7.52 (1H, m), 7.73 (1H, s), 8 , 87 (1H, d, J = 8.5 Hz), 11.15 (1H, sa).

120  120
Rex292 RMN lH (CDCI3): 3,00 (3H, d, J = 4,9Hz), 4,19 (2H, s.a.), 5,92 (1H, s.a.), 6,80 (1H, dd, J = 1,7 Hz, 7,6 Hz), 6,87 (1H, dd, J = 1,7 Hz, 7,6 Hz), 7,08 (1H, d, J = 7,6 Hz).  Rex292 NMR lH (CDCI3): 3.00 (3H, d, J = 4.9Hz), 4.19 (2H, sa), 5.92 (1H, sa), 6.80 (1H, dd, J = 1.7 Hz, 7.6 Hz), 6.87 (1H, dd, J = 1.7 Hz, 7.6 Hz), 7.08 (1H, d, J = 7.6 Hz).

121  121
Rex4 rMn -|H (CDCI3): 3,06 (3H, s), 5,57 (1H, s.a.), 6,04 (1H, s.a.), 7,42 (1H, d, J = 8,1H), 7,74 (1H, dd, J = 1,5 Hz, 7,6H), 7,83 (1H, dd, J = 2,0 Hz, 8,1 Hz).  Rex4 rMn - | H (CDCI3): 3.06 (3H, s), 5.57 (1H, sa), 6.04 (1H, sa), 7.42 (1H, d, J = 8.1H) , 7.74 (1H, dd, J = 1.5 Hz, 7.6H), 7.83 (1H, dd, J = 2.0 Hz, 8.1 Hz).

122  122
Rex353 RMN 1H (CDCI3): 1,31 (3H, t, J = 7,6 Hz), 2,91 (2H, q, J = 7,3 Hz), 3,04 (3H, d, J = 4,9Hz), 5,56 (1H, s.a.), 5,95 (1H, s.a.), 7,21 (1H, m), 7,34 (1H, m), 7,74 (1H, s.a.), 8,56 (1H, m), 11,40 (1H, s.a.).  Rex353 1H NMR (CDCI3): 1.31 (3H, t, J = 7.6 Hz), 2.91 (2H, q, J = 7.3 Hz), 3.04 (3H, d, J = 4 , 9Hz), 5.56 (1H, sa), 5.95 (1H, sa), 7.21 (1H, m), 7.34 (1H, m), 7.74 (1H, sa), 8 , 56 (1H, m), 11.40 (1H, sa).

123  123
Rex299 RMN lH (DMSO-d6): 2,84 (3H, s), 7,21 (2H, t, J = 9,6H), 7,52 (1H, t, J = 9,6 Hz), 7,53 (2H, s), 7,64 (1H, d, J = 4,0 Hz), 8,22 (2H, d, J = 9,2 Hz), 9,24 (1H, d, J = 4,0 Hz), 12,92 (1H, s.a.), 13,73 (1H, s).  Rex299 NMR lH (DMSO-d6): 2.84 (3H, s), 7.21 (2H, t, J = 9.6H), 7.52 (1H, t, J = 9.6 Hz), 7 , 53 (2H, s), 7.64 (1H, d, J = 4.0 Hz), 8.22 (2H, d, J = 9.2 Hz), 9.24 (1H, d, J = 4.0 Hz), 12.92 (1H, sa), 13.73 (1H, s).

124  124
Rex298 ESI-: 343  Rex298 ESI-: 343

125  125
Rex353 ESI-: 325  Rex353 ESI-: 325

126  126
Rex353 ESI-: 398  Rex353 ESI-: 398

127  127
Rex353 ESI+: 334  Rex353 ESI +: 334

[Tabla 601[Table 601

Rex  Rex
Sin Datos  No data

128  128
Rex353 RMN lH (DMSO-d6): 1,24 (3H, t, J = 7,6 Hz), 2,89 (2H, q, J = 7,3 Hz), 4,53 (2H, s), 6,92 (1H, d, J = 8,5 Hz), 7,11-7,16 (2H, m), 8,02 (1H, s.a.), 8,25 (1H, s.a.), 10,78 (1H, s.a.), 11,06 (1H, s.a.).  Rex353 NMR lH (DMSO-d6): 1.24 (3H, t, J = 7.6 Hz), 2.89 (2H, q, J = 7.3 Hz), 4.53 (2H, s), 6.92 (1H, d, J = 8.5 Hz), 7.11-7.16 (2H, m), 8.02 (1H, sa), 8.25 (1H, sa), 10.78 (1H, sa), 11.06 (1H, sa).

129  129
Rex353 ESI-: 265  Rex353 ESI-: 265

130  130
Rex353 ESI-: 350  Rex353 ESI-: 350

131  131
Rex353 ESI-: 289  Rex353 ESI-: 289

132  132
Rex353 ESI+: 488  Rex353 ESI +: 488

133  133
Rex353 RMN lH (CDCI3): 1,31 (3H, t, J = 7,2 Hz), 2,64 (6H, s), 2,91 (2H, q, J = 7,2H), 4,30 (1H, s.a.), 5,60 (1H, s.a.), 7,56 (1H, s.a.), 7,77 (1H, m), 7,95 (1H, d, J = 8,0 Hz), 11,12 (1H, s.a.).  Rex353 1 H NMR (CDCI3): 1.31 (3H, t, J = 7.2 Hz), 2.64 (6H, s), 2.91 (2H, q, J = 7.2H), 4.30 (1H, sa), 5.60 (1H, sa), 7.56 (1H, sa), 7.77 (1H, m), 7.95 (1H, d, J = 8.0 Hz), 11 , 12 (1H, sa).

134  134
Rex353 RMN iH (CDCI3): 1,30 (3h, t, J = 7,2 Hz), 2,89 (2H, q, J = 7,6 Hz), 2,99 (3H, s), 5,59 (1H, s.a.), 6,60 (1H, s.a.), 7,53 (1H, dd, J = 2,4H, 9,2 Hz), 7,60 (1H, d, J = 8,8 Hz), 7,75 (1H, s.a.), 7 96 (1H, d, J = 2,4 Hz), 10,95(1H, s).  Rex353 NMR iH (CDCI3): 1.30 (3h, t, J = 7.2 Hz), 2.89 (2H, q, J = 7.6 Hz), 2.99 (3H, s), 5, 59 (1H, sa), 6.60 (1H, sa), 7.53 (1H, dd, J = 2.4H, 9.2 Hz), 7.60 (1H, d, J = 8.8 Hz ), 7.75 (1H, sa), 7 96 (1H, d, J = 2.4 Hz), 10.95 (1H, s).

135  135
Rex353 ESI+: 368  Rex353 ESI +: 368

Rex  Rex
Sin Datos  No data

136  136
Rex353 ESI+: 364  Rex353 ESI +: 364

137  137
Rex292 RMN 1H (CDCI3): 2,44(3H, s), 2,50 (3H, s), 6,79 (1H, dd, J = 2,4 Hz, 8,4 Hz), 7,06 (1H, d, J = 8,4 Hz), 7,25 (1H, d, J = 2,4 Hz).  Rex292 1 H NMR (CDCI3): 2.44 (3H, s), 2.50 (3H, s), 6.79 (1H, dd, J = 2.4 Hz, 8.4 Hz), 7.06 ( 1H, d, J = 8.4 Hz), 7.25 (1H, d, J = 2.4 Hz).

138  138
Rex353 ESI-: 382  Rex353 ESI-: 382

139  139
Rex292 RMN 1H (CDCI3): 3,15-3,17 (4H, m), 3,70-3,72 (4H, m), 3,85 (3H, s), 4,13 (2H, s.a.), 6,19 (1H, d, J = 2,0 Hz), 6,23 (1H, dd, J = 2,0 Hz, 8,4 Hz), 7,01 (1H, d, J = 8,4 Hz).  Rex292 1H NMR (CDCI3): 3.15-3.17 (4H, m), 3.70-3.72 (4H, m), 3.85 (3H, s), 4.13 (2H, sa) , 6.19 (1H, d, J = 2.0 Hz), 6.23 (1H, dd, J = 2.0 Hz, 8.4 Hz), 7.01 (1H, d, J = 8, 4 Hz)

140  140
Rex41 RMN 'H (CDCls): 3,28-3,30 (4H, m), 3,72-3,74 (4H, m), 4,06 (3H, s), 7,86 (1H, d, J = 2,0 Hz), 7,89 (1H, dd, J = 2,0 Hz, 8,4 Hz), 8,80 (1H, d, J = 8,4 Hz,).  Rex41 NMR 'H (CDCls): 3.28-3.30 (4H, m), 3.72-3.74 (4H, m), 4.06 (3H, s), 7.86 (1H, d , J = 2.0 Hz), 7.89 (1H, dd, J = 2.0 Hz, 8.4 Hz), 8.80 (1H, d, J = 8.4 Hz,).

[Tabla 61][Table 61]

Rex  Rex
Sin Datos  No data

141  141
Rex353 ESI-: 454  Rex353 ESI-: 454

142  142
Rex353 RMN 1H (DMSO-d6): 1,24 (3H, t, J = 7,6 Hz), 2,79 (2H, q, J = 7,3 Hz), 4,56 (2H, s), 6,84 (1H, d, J = 8,5 Hz), 6,98 (1H, dd, J = 2,4 Hz, 8,5 Hz), 7,46 (1H, d, J = 2,2 Hz), 8,01 (1H, s.a.), 8,24 (1H, s.a.), 10,65 (1H, s.a.), 11,11 (1H, s.a.).  Rex353 1 H NMR (DMSO-d6): 1.24 (3H, t, J = 7.6 Hz), 2.79 (2H, q, J = 7.3 Hz), 4.56 (2H, s), 6.84 (1H, d, J = 8.5 Hz), 6.98 (1H, dd, J = 2.4 Hz, 8.5 Hz), 7.46 (1H, d, J = 2.2 Hz), 8.01 (1H, sa), 8.24 (1H, sa), 10.65 (1H, sa), 11.11 (1H, sa).

143  143
Rex353 ESI+: 317  Rex353 ESI +: 317

144  144
Rex353 RMN 1H (DMSO-d6): 1,24 (3H, t, J = 7,6 Hz), 2,78 (2H, q, J = 7,3 Hz), 4,20-4,24 (4H, m), 6,81-6,89 (2H, m), 7,29 (1H, d, J = 2,4 Hz), 7,98 (1H, s.a.), 8,21 (1H, s.a.), 10,98 (1H, s.a.).  Rex353 1H NMR (DMSO-d6): 1.24 (3H, t, J = 7.6 Hz), 2.78 (2H, q, J = 7.3 Hz), 4.20-4.24 (4H , m), 6.81-6.89 (2H, m), 7.29 (1H, d, J = 2.4 Hz), 7.98 (1H, sa), 8.21 (1H, sa) , 10.98 (1H, sa).

145  145
Rex48 RMN 1H (CDCla): 3,36 (3H, s), 3,53 (2H, t, J = 5,1 Hz), 3,61 (2h, m), 4,01 (2H, s.a.), 6,14 (1H, s.a.), 6,76 (1H, dd, J = 2,0 Hz, 8,3 Hz), 6,91 (1H, d, J = 2,2 Hz), 7,33 (1H, d, J = 8,3 Hz).  Rex48 1H NMR (CDCla): 3.36 (3H, s), 3.53 (2H, t, J = 5.1 Hz), 3.61 (2h, m), 4.01 (2H, sa), 6.14 (1H, sa), 6.76 (1H, dd, J = 2.0 Hz, 8.3 Hz), 6.91 (1H, d, J = 2.2 Hz), 7.33 ( 1H, d, J = 8.3 Hz).

146  146
Rex353 RMN lH (CDCl3): 1,31 (3H, t, j' = 7,6 Hz), 2,90 (2H, q, J = 7,3 Hz), 3,39 (3H, s), 3,58 (2H, m), 3,64 (2H, m), 5,79 (1H, s.a.), 6,38 (1H, s.a.), 7,52 (1H, d, J = 3,7 Hz), 7,75 (1H, s.a.), 7,87 (1H, dd, J =2,0 Hz, 8,3 Hz), 11,05 (1H, s.a.).  Rex353 1 H NMR (CDCl3): 1.31 (3H, t, j '= 7.6 Hz), 2.90 (2H, q, J = 7.3 Hz), 3.39 (3H, s), 3 , 58 (2H, m), 3.64 (2H, m), 5.79 (1H, sa), 6.38 (1H, sa), 7.52 (1H, d, J = 3.7 Hz) , 7.75 (1H, sa), 7.87 (1H, dd, J = 2.0 Hz, 8.3 Hz), 11.05 (1H, sa).

147  147
Rex353 RMN 1H (CDCls): 1,24-1,59 (9H, m), 2,90 (2H, q, J = 7,6 Hz), 3,10-3,17 (4H, m), 3,95 (3H, s), 5,59 (1H, s.a.), 7,13 (1H, d, J = 8,8 Hz), 7,63 (1H, d, J = 8,4 Hz), 7,75-7,81 (3H, m), 11,16 (1H, s.a.).  Rex353 1 H NMR (CDCls): 1.24-1.59 (9H, m), 2.90 (2H, q, J = 7.6 Hz), 3.10-3.17 (4H, m), 3 , 95 (3H, s), 5.59 (1H, sa), 7.13 (1H, d, J = 8.8 Hz), 7.63 (1H, d, J = 8.4 Hz), 7 , 75-7.81 (3H, m), 11.16 (1H, sa).

148  148
Rex353 RMN 1H (CDCla): 1,25 (3H, t, J = 7,6 Hz), 2,60 (3H, s), 2,92 (2H, q, J = 7,6 Hz), 5,59 (1H, s.a.), 7,28 (1H, m), 7,73 (1H, s.a.), 7,75 (1H, m), 8,44 (1H, d, J = 2,0 Hz), 10,99 (1H, s.a.).  Rex353 1H NMR (CDCla): 1.25 (3H, t, J = 7.6 Hz), 2.60 (3H, s), 2.92 (2H, q, J = 7.6 Hz), 5, 59 (1H, sa), 7.28 (1H, m), 7.73 (1H, sa), 7.75 (1H, m), 8.44 (1H, d, J = 2.0 Hz), 10.99 (1H, sa).

149  149
Rex353 RMN 1H (CdC|3): 1,21-1,34 (3h, m),' 2,82-2,92 (5H, m), 5,61 (1H, s.a.), 7,51 (1H, d, J = 6,8 Hz), 7,727,75 (1H, m), 7,87 (1H, d, J = 6,8 Hz), 8,42 (1H, d, J = 2,8 Hz), 10,99 (1H, s.a.).  Rex353 1H NMR (CdC | 3): 1.21-1.34 (3h, m), 2.82-2.92 (5H, m), 5.61 (1H, sa), 7.51 (1H , d, J = 6.8 Hz), 7.727.75 (1H, m), 7.87 (1H, d, J = 6.8 Hz), 8.42 (1H, d, J = 2.8 Hz ), 10.99 (1H, sa).

5 ______________________________________[Tabla 62]5 ______________________________________ [Table 62]

Rex  Rex
Sin Datos  No data

150  150
Rex353 ESI+: 364  Rex353 ESI +: 364

151  151
Rex353 RMN 1H (CDCI3): 1,25 (3H, t, J = 7,6 Hz), 2,92 (3H, q, J = 7,6 Hz), 5,63 (1H, s.a.), 7,53 (1H, dd, J = 3,6 Hz, 6,9Hz), 7,76 (1H, s.a.), 7,90 (1H, d, J = 6,0 Hz), 8,78 (1H, d, J = 3,6 Hz), 11,27 (1H, s.a.).  Rex353 1 H NMR (CDCI3): 1.25 (3H, t, J = 7.6 Hz), 2.92 (3H, q, J = 7.6 Hz), 5.63 (1H, sa), 7, 53 (1H, dd, J = 3.6 Hz, 6.9Hz), 7.76 (1H, sa), 7.90 (1H, d, J = 6.0 Hz), 8.78 (1H, d , J = 3.6 Hz), 11.27 (1H, sa).

152  152
Rex353 ESI+: 329  Rex353 ESI +: 329

153  153
Rex353 RMN 1H (CDCI3): 1,34 (3H, t, J = 7,6 Hz), 2,95 (2H, q, J = 7,6 Hz), 5,65 (1H, s.a.), 7,74 (1H, dd, J = 2,0 Hz, 9,2 Hz), 7,79 (1H, s.a.), 8,02 (1H, d, J = 9,2 Hz), 9,28 (1H, d, J = 2,0 Hz), 11,25 (1H, s.a.).  Rex353 1H NMR (CDCI3): 1.34 (3H, t, J = 7.6 Hz), 2.95 (2H, q, J = 7.6 Hz), 5.65 (1H, sa), 7, 74 (1H, dd, J = 2.0 Hz, 9.2 Hz), 7.79 (1H, sa), 8.02 (1H, d, J = 9.2 Hz), 9.28 (1H, d, J = 2.0 Hz), 11.25 (1H, sa).

154  154
Rex353 RMN 1H (CDCI3): 1,30 (3H, t,' J = 7,6 Hz), 2,86 (2H, q, J = 7,6 Hz), 3,79 (3H, s), 5,49 (1H, m), 6,44 (1H, d, J = 3,2 Hz), 7,01 (1H, d, J = 3,2 Hz), 7,15 (1H, dd, J = 0,2 Hz, 8,4 Hz), 7,54 (1H, d, J = 8,4 Hz), 7,74 (1H, m), 7,98 (1H, s), 10,84 (1H, m).  Rex353 1H NMR (CDCI3): 1.30 (3H, t, 'J = 7.6 Hz), 2.86 (2H, q, J = 7.6 Hz), 3.79 (3H, s), 5 , 49 (1H, m), 6.44 (1H, d, J = 3.2 Hz), 7.01 (1H, d, J = 3.2 Hz), 7.15 (1H, dd, J = 0.2 Hz, 8.4 Hz), 7.54 (1H, d, J = 8.4 Hz), 7.74 (1H, m), 7.98 (1H, s), 10.84 (1H , m).

155  155
Rex292 rMn 1H (CdC3): 2,84 (3h, s), 3,37 (2H, s.a.), 3,99 (1H, s.a.), 6,62 (1H, d, J = 8,4 Hz), 6,82 (1H, dd, J = 2,8 Hz, 8,4 Hz), 6,86 (1H, d, J = 2,8 Hz).  Rex292 rMn 1H (CdC3): 2.84 (3h, s), 3.37 (2H, sa), 3.99 (1H, sa), 6.62 (1H, d, J = 8.4 Hz), 6.82 (1H, dd, J = 2.8 Hz, 8.4 Hz), 6.86 (1H, d, J = 2.8 Hz).

156  156
Rex353 RMN 1H (CDCI3): 1,28 (3H, t, J = 7,6 Hz), 2,85 (2H, q, J = 7,6 Hz), 2,91 (3H, d, J = 4,8 Hz), 4,32 (1H, s.a.), 5,51 (1H, s.a.), 6,73 (1H, d, J = 8,4 Hz), 7,66-7,70 (3H, m), 10,50 (1H, s.a.).  Rex353 1H NMR (CDCI3): 1.28 (3H, t, J = 7.6 Hz), 2.85 (2H, q, J = 7.6 Hz), 2.91 (3H, d, J = 4 , 8 Hz), 4.32 (1H, sa), 5.51 (1H, sa), 6.73 (1H, d, J = 8.4 Hz), 7.66-7.70 (3H, m ), 10.50 (1H, sa).

157  157
Rex292 RMN 1H (DMSO-d6): 1,67-1,78 (2H, m), 2,07 (2H, m), 3,03-3,27 (8H, m), 3,73 (3h, s), 3,90-4,16 (3H, m), 5,79 (2H, s.a.), 6,29 (1H, d, J = 8,5 Hz), 6,50-6,54 (2H, m).  Rex292 1H NMR (DMSO-d6): 1.67-1.78 (2H, m), 2.07 (2H, m), 3.03-3.27 (8H, m), 3.73 (3h, s), 3.90-4.16 (3H, m), 5.79 (2H, sa), 6.29 (1H, d, J = 8.5 Hz), 6.50-6.54 (2H , m).

158  158
Rex503 ESI+: 338  Rex503 ESI +: 338

159  159
Rex353 ESI+: 491  Rex353 ESI +: 491

160  160
Rex160 RMN 1H (CDCI3): 1,35(3H, t, J = 7,6 Hz), 3,02 (2H, q, J=7,6 Hz).  Rex160 1H NMR (CDCI3): 1.35 (3H, t, J = 7.6 Hz), 3.02 (2H, q, J = 7.6 Hz).

161  161
Rex353 ESI+: 375  Rex353 ESI +: 375

[Tabla 63][Table 63]

Rex  Rex
Sin Datos  No data

162  162
Rex292 ESI+: 276  Rex292 ESI +: 276

163  163
Rex444 ESI+: 306  Rex444 ESI +: 306

164  164
Rex353 ESI+: 459  Rex353 ESI +: 459

165  165
Rex353 ESI+: 376  Rex353 ESI +: 376

166  166
Rex353 RMN 1H (CDCI3): 1,28(3H, t, J = 7,6 Hz), 2,84 (2H, q, J = 7,6 Hz), 3,46-3,48 (4H, m), 3,83-3,85 (4H, m), 5,55 (1H, s.a.), 6,67 (1H, d, J = 8,8 Hz), 8,43 (1H, d, J = 2,4 Hz), 10,45 (1H, s.a.).  Rex353 1H NMR (CDCI3): 1.28 (3H, t, J = 7.6 Hz), 2.84 (2H, q, J = 7.6 Hz), 3.46-3.48 (4H, m ), 3.83-3.85 (4H, m), 5.55 (1H, sa), 6.67 (1H, d, J = 8.8 Hz), 8.43 (1H, d, J = 2.4 Hz), 10.45 (1H, sa).

167  167
Rex292 ESI+: 276  Rex292 ESI +: 276

168  168
Rex444 ESI+: 306  Rex444 ESI +: 306

Rex  Rex
Sin Datos  No data

169  169
Rex353 ESI+: 459  Rex353 ESI +: 459

170  170
Rex353 ESI+: 552  Rex353 ESI +: 552

171  171
Rex353 RMN 'H (CDCI3): 1,28 (3H, t, J = 7,2 Hz), 2,84 (2H, q, J = 7,2 Hz), 3,12-3,14 (4H, m), 3,86-3,88 (4H, m), 5,51 (1H, s.a.), 6,91 (1H, dd, J = 2,4 Hz, 7,2 Hz), 7,55 (1H, dd, J = 2,4 Hz, 7,2 Hz), 7,71 (1H, s.a.), 10,58 (1H, s.a.).  Rex353 NMR 'H (CDCI3): 1.28 (3H, t, J = 7.2 Hz), 2.84 (2H, q, J = 7.2 Hz), 3.12-3.14 (4H, m), 3.86-3.88 (4H, m), 5.51 (1H, sa), 6.91 (1H, dd, J = 2.4 Hz, 7.2 Hz), 7.55 ( 1H, dd, J = 2.4 Hz, 7.2 Hz), 7.71 (1H, sa), 10.58 (1H, sa).

172  172
Rex353 RMN ’H (CDCI3): 1,28 (3H, t, J = 7,6 Hz), 2,31 (3H, s), 2,36 (3H, s), 2,84 (2H, q, J = 7,6 Hz), 2,922,94 (4H, m), 5,48 (1H, s.a.), 7,02 (1H, d, J = 8,8 Hz), 7,34 (1H, d, J = 2,4 Hz), 7,55 (1H, dd, J = 2,7 Hz, 8,5 Hz), 7,71 (1H, s.a.), 10,60 (1H, s.a.).  Rex353 NMR 'H (CDCI3): 1.28 (3H, t, J = 7.6 Hz), 2.31 (3H, s), 2.36 (3H, s), 2.84 (2H, q, J = 7.6 Hz), 2,922.94 (4H, m), 5.48 (1H, sa), 7.02 (1H, d, J = 8.8 Hz), 7.34 (1H, d, J = 2.4 Hz), 7.55 (1H, dd, J = 2.7 Hz, 8.5 Hz), 7.71 (1H, sa), 10.60 (1H, sa).

173  173
Rex353 RMN 1H (CdCI3): 1,28 (3H, t, J = 7,6 Hz), 1,68-1,74 (6H, m), 1,92-1,95 (2H, m), 2,29-2,36 (7H, m), 2,50-2,65 (8H, m), 2,84 (2H, q, J = 7,6 Hz), 3,13-3,16 (2H, m), 5,54 (1H, s.a.), 6,98 (1H, d, J = 6,5 Hz), 7,33 (1H, d, J = 2,6 Hz), 7,51 (1H, d, J = 2,7 Hz), 7,71 (1H, s.a.), 10,58 (1H, s.a.).  Rex353 1H NMR (CdCI3): 1.28 (3H, t, J = 7.6 Hz), 1.68-1.74 (6H, m), 1.92-1.95 (2H, m), 2 , 29-2.36 (7H, m), 2.50-2.65 (8H, m), 2.84 (2H, q, J = 7.6 Hz), 3.13-3.16 (2H , m), 5.54 (1H, sa), 6.98 (1H, d, J = 6.5 Hz), 7.33 (1H, d, J = 2.6 Hz), 7.51 (1H , d, J = 2.7 Hz), 7.71 (1H, sa), 10.58 (1H, sa).

[Tabla 641[Table 641

Rex  Rex
Sin Datos  No data

174  174
Rex353 RMN 1H (CDCI3): 1,29 (3H, t, J = 7,3 Hz), 2,37 (3H, s), 2,62 (4H, m), 2,85 (2H, q, J = 7,3 Hz), 3,03 (4H, m), 5,53 (1H, s.a.), 7,05 (1H, d, J = 8,8 Hz), 7,51 (1H, dd, J = 2,7 Hz, 8,8 Hz), 7,72 (1H, d, J = 2,4 Hz), 10,70 (1H, s.a.).  Rex353 1H NMR (CDCI3): 1.29 (3H, t, J = 7.3 Hz), 2.37 (3H, s), 2.62 (4H, m), 2.85 (2H, q, J = 7.3 Hz), 3.03 (4H, m), 5.53 (1H, sa), 7.05 (1H, d, J = 8.8 Hz), 7.51 (1H, dd, J = 2.7 Hz, 8.8 Hz), 7.72 (1H, d, J = 2.4 Hz), 10.70 (1H, sa).

175  175
Rex353 RMN 1H (CDCI3): 1,28 (t, J = 7,2 Hz, 3H), 1,49 (s, 9H), 2,84 ( q, J = 7,2 Hz, 2H), 3,09 (m, 4H), 3,58 (m, 4H), 5,62 (s.a.,1H), 6,92 (d, J=9,2 Hz, 2H), 7,54 (d, J=9,2 Hz, 2H), 7,7 1 (s.a., 1H), 10,60 (s, 1H).  Rex353 1H NMR (CDCI3): 1.28 (t, J = 7.2 Hz, 3H), 1.49 (s, 9H), 2.84 (q, J = 7.2 Hz, 2H), 3, 09 (m, 4H), 3.58 (m, 4H), 5.62 (sa, 1H), 6.92 (d, J = 9.2 Hz, 2H), 7.54 (d, J = 9 , 2 Hz, 2H), 7.7 1 (sa, 1H), 10.60 (s, 1H).

176  176
Rex292 RMN 1H (CdC|3): 1,60 (2H, s.a.), 2,04-2,17 (4h, m), 2,91-2,94 (4H, m), 6,80 (1H, dd, J = 2,8 Hz, 8,4 Hz), 6,91 (1H, d, J = 2,8 Hz), 7,17 (1H, d, J = 8,4H).  Rex292 1H NMR (CdC | 3): 1.60 (2H, sa), 2.04-2.17 (4h, m), 2.91-2.94 (4H, m), 6.80 (1H, dd, J = 2.8 Hz, 8.4 Hz), 6.91 (1H, d, J = 2.8 Hz), 7.17 (1H, d, J = 8.4H).

177  177
Rex516 rMn 1H (CDCI3): 2,13-2,22’ (4H, m), 3,18-3,20 (4H, m), 7,36 (1H, d, J = 8,8 Hz), 8,35 (1H, dd, J = 2,4 Hz, 9,2 Hz), 8,53 (1H, d, J = 2,4 Hz).  Rex516 rMn 1H (CDCI3): 2.13-2.22 '(4H, m), 3.18-3.20 (4H, m), 7.36 (1H, d, J = 8.8 Hz), 8.35 (1H, dd, J = 2.4 Hz, 9.2 Hz), 8.53 (1H, d, J = 2.4 Hz).

178  178
Rex353 ESI-: 462  Rex353 ESI-: 462

179  179
Rex353 ESI+: 400  Rex353 ESI +: 400

180  180
Rex292 RMN 1H (CDCI3): 0,16-0,20 (2H, m), 0,55-0,59 (2H, m), 0,97 (1H, m), 2,40 (2H, d, J = 6,4 Hz), 2,75 (2H, m), 2,96 (4H, m), 3,72 (2H, m), 6,79 (1H, dd, J = 2,8 Hz, 8,4 Hz), 6,89 (1H, d, J = 2,8 Hz), 7,24 (1H, d, J = 8,4 Hz).  Rex292 1H NMR (CDCI3): 0.16-0.20 (2H, m), 0.55-0.59 (2H, m), 0.97 (1H, m), 2.40 (2H, d, J = 6.4 Hz), 2.75 (2H, m), 2.96 (4H, m), 3.72 (2H, m), 6.79 (1H, dd, J = 2.8 Hz, 8.4 Hz), 6.89 (1H, d, J = 2.8 Hz), 7.24 (1H, d, J = 8.4 Hz).

181  181
Rex516 EI: 329  Rex516 EI: 329

182  182
Rex353 ESI+: 483  Rex353 ESI +: 483

183  183
Rex292 RMN 1H (CDCI3): 1,80-1,88 (1H, m), 2,06-2,14 (1H, m), 2,24 (6H, s), 2,85-3,20 (5H, m), 3,65 (2H, s.a.), 6,78 (1H, dd, J = 2,9Hz, 8,5 Hz), 6,90 (1H, d, J = 2,7 Hz), 7,14 (1H, d, J = 8,5 Hz).  Rex292 1H NMR (CDCI3): 1.80-1.88 (1H, m), 2.06-2.14 (1H, m), 2.24 (6H, s), 2.85-3.20 ( 5H, m), 3.65 (2H, sa), 6.78 (1H, dd, J = 2.9Hz, 8.5Hz), 6.90 (1H, d, J = 2.7Hz), 7.14 (1H, d, J = 8.5 Hz).

5 ______________________________________[Tabla 6515 ______________________________________ [Table 651

Rex  Rex
Sin Datos  No data

184  184
Rex516 RMN 1H (CDCI3): 1,90-1,97 (1H, m), 2,21-2,29 (1H, m), 2,32 (3H, s), 2,77-2,82 (1H, m), 3,43-3,53 (1H, m), 3,62-3,67 (3H, m), 6,79 (1H, d, J = 9,5 Hz), 8,16 (1H, dd, J = 2,7 Hz, 9,5 Hz), 8,53 (1H, d, J = 2,7 Hz).  Rex516 1H NMR (CDCI3): 1.90-1.97 (1H, m), 2.21-2.29 (1H, m), 2.32 (3H, s), 2.77-2.82 ( 1H, m), 3.43-3.53 (1H, m), 3.62-3.67 (3H, m), 6.79 (1H, d, J = 9.5 Hz), 8.16 (1H, dd, J = 2.7 Hz, 9.5 Hz), 8.53 (1H, d, J = 2.7 Hz).

185  185
Rex353 RMN 1H (CDCI3): 1,29 (3H, t, J = 7,3 Hz), 1,84-1,89 (1H, m), 2,12-2,16 (1H, m), 2,26 (6H, s), 2,832,89 (3H, m), 3,20-3,41 (4H, m), 5,57 (1H, s.a.), 7,09 (1H, d, J = 8,8 Hz), 7,71-7,82 (3H, m), 10,68 (1H, s.a.).  Rex353 1H NMR (CDCI3): 1.29 (3H, t, J = 7.3 Hz), 1.84-1.89 (1H, m), 2.12-2.16 (1H, m), 2 , 26 (6H, s), 2,832.89 (3H, m), 3.20-3.41 (4H, m), 5.57 (1H, sa), 7.09 (1H, d, J = 8 , 8 Hz), 7.71-7.82 (3H, m), 10.68 (1H, sa).

186  186
Rex353 RMN 1H (CDCI3): 1,10-1,15 (3H, m), 1,30 (3H, t, J = 7,3 Hz), 2,45-2,52 (2H, m), 2,85-2,97 (10H, m), 5,57 (1H, s.a.), 7,37-7,39 (1H, m), 7,73 (1H, s.a.), 7,87-7,88 (2H, m), 10,86 (1 H, s.a.).  Rex353 1 H NMR (CDCI3): 1.10-1.15 (3H, m), 1.30 (3H, t, J = 7.3 Hz), 2.45-2.52 (2H, m), 2 , 85-2.97 (10H, m), 5.57 (1H, sa), 7.37-7.39 (1H, m), 7.73 (1H, sa), 7.87-7.88 (2H, m), 10.86 (1 H, sa).

187  187
Rex292 RMN 1H (CdC|3): 1,04 (6H, d, J = 6,3 Hz), 2,28-2,33 (2H, m), 2,81 (2H, dd,' J = 2,0 Hz, 9,0 Hz), 3,023,07 (2H, m), 3,69 (2H, s.a.), 6,78 (1H, dd, J = 2,7 Hz, 8,5 Hz), 6,89 (1H, d, J = 2,9Hz), 7,15 (1H, d, J = 8,5 Hz).  Rex292 1H NMR (CdC | 3): 1.04 (6H, d, J = 6.3 Hz), 2.28-2.33 (2H, m), 2.81 (2H, dd, 'J = 2 , 0 Hz, 9.0 Hz), 3.023.07 (2H, m), 3.69 (2H, sa), 6.78 (1H, dd, J = 2.7 Hz, 8.5 Hz), 6 , 89 (1H, d, J = 2.9Hz), 7.15 (1H, d, J = 8.5Hz).

188  188
Rex516 RMN 1H (CDCI3): 1,10(3H, s), 1,11 (3H, s), 2,48-2,53 (2H, m), 3,08-3,13 (2H, m), 3,22 (2H, d, J = 10,7 Hz), 7,22 (1H, d, J = 9,0 Hz), 8,29 (1H, dd, J = 2,7 Hz, 9,0 Hz), 8,50 (1H, d, J = 2,7 Hz).  Rex516 1H NMR (CDCI3): 1.10 (3H, s), 1.11 (3H, s), 2.48-2.53 (2H, m), 3.08-3.13 (2H, m) , 3.22 (2H, d, J = 10.7 Hz), 7.22 (1H, d, J = 9.0 Hz), 8.29 (1H, dd, J = 2.7 Hz, 9, 0 Hz), 8.50 (1H, d, J = 2.7 Hz).

189  189
Rex353 RMN 1H (CDCI3): 1,05-1,09 (6H, m), 1,22-1,46 (3H, m), 2,34-2,40 (2H, m), 2,71-3,76 (6H, m), 5,57 (1H, s.a.), 7,32 (1H, d, J = 8,5 Hz), 7,74 (1H, s.a.), 7,85-7,88 (2H, m), 10,85 (1H, s.a.).  Rex353 1 H NMR (CDCI3): 1.05-1.09 (6H, m), 1.22-1.46 (3H, m), 2.34-2.40 (2H, m), 2.71- 3.76 (6H, m), 5.57 (1H, sa), 7.32 (1H, d, J = 8.5 Hz), 7.74 (1H, sa), 7.85-7.88 (2H, m), 10.85 (1H, sa).

[Tabla 661[Table 661

Rex  Rex
Sin Datos  No data

190  190
Rex292 RMN 1H (CDCI3): 1,41 (3H, s), 1,42 (3H, s), 2,68 (3H, s), 2,87-2,90 (2H, m), 2,81 (2H, dd, J = 2,0 Hz, 9,0 Hz,2H),3,00(m,2H),3,23(m,2H),3,81 (s.a.), 6,80 (1H, dd, J = 2,9Hz, 8,5 Hz), 6,88 (1H, d, J = 2,9Hz), 7,24 (1H, d, J = 7,8 Hz).  Rex292 1H NMR (CDCI3): 1.41 (3H, s), 1.42 (3H, s), 2.68 (3H, s), 2.87-2.90 (2H, m), 2.81 (2H, dd, J = 2.0 Hz, 9.0 Hz, 2H), 3.00 (m, 2H), 3.23 (m, 2H), 3.81 (sa), 6.80 (1H , dd, J = 2.9Hz, 8.5Hz), 6.88 (1H, d, J = 2.9Hz), 7.24 (1H, d, J = 7.8Hz).

191  191
Rex516 RMN 1H (CDCI3): 1,15 (3H, s), 1,16 (3H, s), 2,36 (3H, s), 2,46-2,50 (2H, m), 2,79-2,85 (2H, m), 3,19 (2H, dd, J = 2,7 Hz, 9,0 Hz), 7,22-7,24 (1H, m), 8,30 (1H, dd, J = 2,7H, 9,0 Hz), 8,50 (1H, d, J = 2,7 Hz).  Rex516 1H NMR (CDCI3): 1.15 (3H, s), 1.16 (3H, s), 2.36 (3H, s), 2.46-2.50 (2H, m), 2.79 -2.85 (2H, m), 3.19 (2H, dd, J = 2.7 Hz, 9.0 Hz), 7.22-7.24 (1H, m), 8.30 (1H, dd, J = 2.7H, 9.0 Hz), 8.50 (1H, d, J = 2.7 Hz).

192  192
Rex353 RMN 1H (CDCI3): 1,11 (6H, m), 1,30 (3H, t, J = 7,3 Hz), 2,33-2,44 (5H, m), 2,67-2,79 (2H, m), 2,852,91 (4H, m), 5,54 (1H, s.a.), 7,33 (1H, d, J = 8,3 Hz), 7,73 (1H, s.a.), 7,85-7,87 (2H, m), 10,85 (1H, s.a.).  Rex353 1H NMR (CDCI3): 1.11 (6H, m), 1.30 (3H, t, J = 7.3 Hz), 2.33-2.44 (5H, m), 2.67-2 , 79 (2H, m), 2,852.91 (4H, m), 5.54 (1H, sa), 7.33 (1H, d, J = 8.3 Hz), 7.73 (1H, sa) , 7.85-7.87 (2H, m), 10.85 (1H, sa).

Rex  Rex
Sin Datos  No data

193  193
Rex353 ESI+: 362  Rex353 ESI +: 362

194  194
Rex194 ESI+: 377  Rex194 ESI +: 377

195  195
Rex353 ESI+: 389  Rex353 ESI +: 389

196  196
Rex353 ESI+: 403  Rex353 ESI +: 403

197  197
Rex353 RMN 'H (CDCl3): 1,30 (3H, t, J = 7,6 Hz), 1,48 (9H, s), 2,76-2,91 (6H, m), 3,55 (4H, m), 5,57 (1H, s.a.), 7,31 (1H, d, J = 8,8 Hz), 7,74 (1H, s.a.), 7,86-7,90 (2H, m), 10,89 (1H, s.a.).  Rex353 NMR 'H (CDCl3): 1.30 (3H, t, J = 7.6 Hz), 1.48 (9H, s), 2.76-2.91 (6H, m), 3.55 ( 4H, m), 5.57 (1H, sa), 7.31 (1H, d, J = 8.8 Hz), 7.74 (1H, sa), 7.86-7.90 (2H, m ), 10.89 (1H, sa).

198  198
Rex353 RMN ’H (CdCI3): 1,28 (3H, t, J = 7,6 Hz), 1,48 (9H, s), 2,32 (3H, s), 2,82-2,88 (6H, m), 3,56 (4H, t, J = 4,9Hz), 5,52 (1H, s.a.), 6,98 (1H, d, J = 8,5 Hz), 7,36 (1H, d, J = 2,7 Hz), 7,55 (1H, dd, J = 2,7 Hz, 8,5 Hz), 7,72 (1H, s.a.), 10,62 (1H, s.a.).  Rex353 NMR 'H (CdCI3): 1.28 (3H, t, J = 7.6 Hz), 1.48 (9H, s), 2.32 (3H, s), 2.82-2.88 ( 6H, m), 3.56 (4H, t, J = 4.9Hz), 5.52 (1H, sa), 6.98 (1H, d, J = 8.5Hz), 7.36 (1H , d, J = 2.7 Hz), 7.55 (1H, dd, J = 2.7 Hz, 8.5 Hz), 7.72 (1H, sa), 10.62 (1H, sa).

[Tabla 671[Table 671

Rex  Rex
Sin Datos  No data

199  199
Rex516 RMN 1H (CDCI3): 0,99 (s, 6H), 1,29 (t, J = 5,6 Hz, 2H), 1,59-1,67 (m, 2H), 2,46 (s, 2H), 2,67 (m, 2H), 3,67 (s.a., 2H), 6,77 (dd, J = 2,9 Hz ,8,5 Hz, 1H), 6,89 (d, J =2,7 Hz, 1H), 7,16 (d, J = 6,5 Hz, 1H).  Rex516 1H NMR (CDCI3): 0.99 (s, 6H), 1.29 (t, J = 5.6 Hz, 2H), 1.59-1.67 (m, 2H), 2.46 (s , 2H), 2.67 (m, 2H), 3.67 (sa, 2H), 6.77 (dd, J = 2.9 Hz, 8.5 Hz, 1H), 6.89 (d, J = 2.7 Hz, 1H), 7.16 (d, J = 6.5 Hz, 1H).

200  200
Rex194 ESI+: 417  Rex194 ESI +: 417

201  201
Rex194 ESI+: 476  Rex194 ESI +: 476

202  202
Rex292 RMN 1H (CDCI3): 1,81-1,85 (2H, m), 1,99-2,03 (2H, m), 2,18-2,21 (4H, m), 2,79-2,84 (2H, m), 3,013,04 (2H, m), 3,12-3,34 (4H, m), 3,66-3,69 (2H, m), 9,92 (1H, dd, J = 2,4 Hz, 8,0 Hz), 6,98 (1H, d, J = 2,4 Hz), 7,24 (1H, d, J = 8,0 Hz).  Rex292 1H NMR (CDCI3): 1.81-1.85 (2H, m), 1.99-2.03 (2H, m), 2.18-2.21 (4H, m), 2.79- 2.84 (2H, m), 3,013.04 (2H, m), 3.12-3.34 (4H, m), 3.66-3.69 (2H, m), 9.92 (1H, dd, J = 2.4 Hz, 8.0 Hz), 6.98 (1H, d, J = 2.4 Hz), 7.24 (1H, d, J = 8.0 Hz).

203  203
Rex516 EI : 343  Rex516 EI: 343

204  204
Rex353 ESI+: 497  Rex353 ESI +: 497

205  205
Rex353 ESI-: 437  Rex353 ESI-: 437

206  206
Rex353 ESI-: 472  Rex353 ESI-: 472

207  207
Rex292 RMN lH (CDCI3): 0,81 (3H, d, J = 6,4 Hz), 1,48 (3H, d, J = 6,6 Hz), 2,68 (2H, q, J = 11,0 Hz), 2,81 (2H, d, J = 4,9Hz), 2,93 (1H, dd, J = 2,9Hz, 12,9Hz), 3,17 (1H, s.a.), 3,29-3,44 (2H, m), 3,87 (2H, s.a.), 6,83 (1H, dd, J = 2,7 Hz, 8,5H), 6,89 (1H, d, J = 2,7 Hz), 7,29 (1H, d, J = 8,3 Hz).  Rex292 1 H NMR (CDCI3): 0.81 (3H, d, J = 6.4 Hz), 1.48 (3H, d, J = 6.6 Hz), 2.68 (2H, q, J = 11 , 0 Hz), 2.81 (2H, d, J = 4.9Hz), 2.93 (1H, dd, J = 2.9Hz, 12.9Hz), 3.17 (1H, sa), 3, 29-3.44 (2H, m), 3.87 (2H, sa), 6.83 (1H, dd, J = 2.7 Hz, 8.5H), 6.89 (1H, d, J = 2.7 Hz), 7.29 (1H, d, J = 8.3 Hz).

208  208
Rex516 RmN 1H (CDCI3): 0,79 (3H, d, J = 6,3 Hz), 1,04 (3H, d, J = 6,4 Hz),' 2,16-2,21 (2H, m), 2,28-2,34 (4H, m), 2,44-2,50 (1H, m), 2,86-2,90 (2H, m), 7,56 (1H, d, J = 8,8 Hz), 8,40 (1H, dd, J = 2,7 Hz, 8,8 Hz), 8,55 (1H, d, J = 2,7 Hz).  Rex516 RmN 1H (CDCI3): 0.79 (3H, d, J = 6.3 Hz), 1.04 (3H, d, J = 6.4 Hz), '2.16-2.21 (2H, m), 2.28-2.34 (4H, m), 2.44-2.50 (1H, m), 2.86-2.90 (2H, m), 7.56 (1H, d, J = 8.8 Hz), 8.40 (1H, dd, J = 2.7 Hz, 8.8 Hz), 8.55 (1H, d, J = 2.7 Hz).

209  209
Rex353 ESI+: 471  Rex353 ESI +: 471

210  210
Rex292 EI: 219  Rex292 EI: 219

211  211
Rex516 EI: 249  Rex516 EI: 249

212  212
Rex353 ESI+: 403  Rex353 ESI +: 403

5 ______________________________________[Tabla 6815 ______________________________________ [Table 681

Rex  Rex
Sin Datos  No data

213  213
Rex292 RMN lH (CDCI3): 1,52-1,55 (2H, m), 2,01 (2H, dt, J = 4,4 Hz, 8,4 Hz), 2,12-2,16 (2H, m), 2,84-2,94 (6H, m), 6,87 (1H, dd, J = 2,4 Hz, 8,4 Hz), 6,94 (1H, d, J = 2,4 Hz), 7,10-7,21 (4H, m), 7,29 (1H, d, J = 8,4 Hz).  Rex292 NMR lH (CDCI3): 1.52-1.55 (2H, m), 2.01 (2H, dt, J = 4.4 Hz, 8.4 Hz), 2.12-2.16 (2H , m), 2.84-2.94 (6H, m), 6.87 (1H, dd, J = 2.4 Hz, 8.4 Hz), 6.94 (1H, d, J = 2, 4 Hz), 7.10-7.21 (4H, m), 7.29 (1H, d, J = 8.4 Hz).

214  214
Rex516 RMN lH (CDCI3): 1,52-1,55 (2H, m), 2,01 (2H, dt, J = 4,4 Hz, 12,8 Hz), 2,12-2,16 (2H, m), 2,84-3,31 (6H, m), 6,86-6,89 (1H, m), 6,95 (1H, m), 7,10-7,19 (4H, m), 7,30 (1H, d, J = 8,4 Hz).  Rex516 NMR lH (CDCI3): 1.52-1.55 (2H, m), 2.01 (2H, dt, J = 4.4 Hz, 12.8 Hz), 2.12-2.16 (2H , m), 2.84-3.31 (6H, m), 6.86-6.89 (1H, m), 6.95 (1H, m), 7.10-7.19 (4H, m ), 7.30 (1H, d, J = 8.4 Hz).

215  215
Rex353 ESI-: 528  Rex353 ESI-: 528

216  216
Rex353 ESI+: 403  Rex353 ESI +: 403

217  217
Rex292 EI: 344  Rex292 EI: 344

218  218
Rex516 EI: 374  Rex516 EI: 374

219  219
Rex353 ESI-: 526  Rex353 ESI-: 526

220  220
Rex292 RMN lH (CDCI3): 2,34 (3H, s), 2,51 (4H, t, J = 4,8 Hz), 3,17 (4H, t, J = 4,8 Hz), 3,63 (2H, s.a.), 6,58 (2H, s).  Rex292 1 H NMR (CDCI3): 2.34 (3H, s), 2.51 (4H, t, J = 4.8 Hz), 3.17 (4H, t, J = 4.8 Hz), 3, 63 (2H, sa), 6.58 (2H, s).

221  221
Rex516 RMN 1H (CDCI3): 2,38 (3H, s), 2,58 (4H, m), 3,36 (4H, t, J = 4,8 Hz), 8,15 (2H, s).  Rex516 1H NMR (CDCI3): 2.38 (3H, s), 2.58 (4H, m), 3.36 (4H, t, J = 4.8 Hz), 8.15 (2H, s).

222  222
Rex353 ESI-: 441  Rex353 ESI-: 441

223  223
Rex292 RMN lH (CDCI3): 1,41-1,53 (10H, m), 1,69 (2H, t, J = 7,1 Hz), 2,86 (2H, s), 3,10 (2H, t, J = 6,8 Hz), 3,59 (2H, s.a.), 6,77 (1H, d, J = 2,7H, 8,5 Hz), 6,90 (1H, dd, J = 2,5 Hz, 9,5 Hz), 7,08 (1H, d, J = 8,8 Hz).  Rex292 1 H NMR (CDCI3): 1.41-1.53 (10H, m), 1.69 (2H, t, J = 7.1 Hz), 2.86 (2H, s), 3.10 (2H , t, J = 6.8 Hz), 3.59 (2H, sa), 6.77 (1H, d, J = 2.7H, 8.5 Hz), 6.90 (1H, dd, J = 2.5 Hz, 9.5 Hz), 7.08 (1H, d, J = 8.8 Hz).

224  224
Rex516 RMN lH (CDCI3): 1,42-1,57 (10H, m), 1,85 (2H, t, J = 7,1 Hz), 3,33 (2H, s), 3,61 (2H, t, J = 7,0 Hz), 6,77 (1H, d, J = 9,5 Hz), 8,14 (1H, dd, J = 2,7 Hz, 9,5 Hz), 8,53 (1H, d, J = 2,9Hz).  Rex516 NMR lH (CDCI3): 1.42-1.57 (10H, m), 1.85 (2H, t, J = 7.1 Hz), 3.33 (2H, s), 3.61 (2H , t, J = 7.0 Hz), 6.77 (1H, d, J = 9.5 Hz), 8.14 (1H, dd, J = 2.7 Hz, 9.5 Hz), 8, 53 (1H, d, J = 2.9Hz).

Rex  Rex
Sin Datos  No data

225  225
Rex353 RMN lH (CDCl3): 1,28 (3H, t, J = 7,6 Hz), 1,43-1,55 (10H, m), 2,32 (3H, s), 1,75 (2H, t, J = 7,1 Hz), 2,85 (2H, q, J = 7,6 Hz), 3,06 (2H, s), 3,32 (2H, t, J = 6,8 Hz), 5,50 (1H, s.a.), 7,02 (1H, d, J = 9,0 Hz), 7,69-7,71 (2H, m), 7,80 (1H, d, J = 2,7 Hz), 10,61 (1H, s.a.).  Rex353 1 H NMR (CDCl3): 1.28 (3H, t, J = 7.6 Hz), 1.43-1.55 (10H, m), 2.32 (3H, s), 1.75 (2H , t, J = 7.1 Hz), 2.85 (2H, q, J = 7.6 Hz), 3.06 (2H, s), 3.32 (2H, t, J = 6.8 Hz ), 5.50 (1H, sa), 7.02 (1H, d, J = 9.0 Hz), 7.69-7.71 (2H, m), 7.80 (1H, d, J = 2.7 Hz), 10.61 (1H, sa).

226  226
Rex353 RMN lH (CDCls): 1,29 (3H, t, J = 7,6 Hz), 1,49 (9h, s), 2,85 (2H, q, J = 7,6 Hz), 2,98 (4H, m), 3,61 (4H, t, J = 5,1 Hz), 3,90 (3H, s), 5,52 (1H, s.a.), 6,87 (1H, d, J = 8,5 Hz), 7,14 (1H, dd, J = 2,4 Hz, 8,5 Hz), 7,38 (1H, d, J = 2,2 Hz), 7,73 (1H, s.a.), 10,70 (1H, s.a.).  Rex353 NMR lH (CDCls): 1.29 (3H, t, J = 7.6 Hz), 1.49 (9h, s), 2.85 (2H, q, J = 7.6 Hz), 2, 98 (4H, m), 3.61 (4H, t, J = 5.1 Hz), 3.90 (3H, s), 5.52 (1H, sa), 6.87 (1H, d, J = 8.5 Hz), 7.14 (1H, dd, J = 2.4 Hz, 8.5 Hz), 7.38 (1H, d, J = 2.2 Hz), 7.73 (1H, sa), 10.70 (1H, sa).

227  227
Rex353 ESI+: 370  Rex353 ESI +: 370

228  228
Rex413 ESI-: 343  Rex413 ESI-: 343

229  229
Rex412 RMN lH (CDCl3): 1,50 (9H, s), 2,37 (2H, m), 3,63-3,65 (2H, m), 4,06 (2H, m), 5,66 (1H, m), 7,44 (1H, d, J = 8,3 Hz), 8,35 (1H, dd, J = 2,2 Hz, 8,3 Hz), 8,54 (1H, d, J = 2,2 Hz).  Rex412 NMR lH (CDCl3): 1.50 (9H, s), 2.37 (2H, m), 3.63-3.65 (2H, m), 4.06 (2H, m), 5.66 (1H, m), 7.44 (1H, d, J = 8.3 Hz), 8.35 (1H, dd, J = 2.2 Hz, 8.3 Hz), 8.54 (1H, d , J = 2.2 Hz).

230  230
Rex353 RMN 1H (CDCl3): 1,30 (3H, t, J = 7,3 Hz), 1,49 ’(9H, s), 1,60-1,78 (2H, m), 2,81 (2H, m), 2,88 (2H, q, J = 7,3 Hz), 3,00-3,06 (1H, m), 4,24 (1H, m), 5,56 (1H, m), 7,37 (1H, d, J = 8,5 Hz), 7,74 (1H, m), 7,85 (1H, dd, J = 2,4 Hz, 8,5 Hz), 7,92 (1H, d, J = 2,4 Hz), 10,90 (1H, s.a.).  Rex353 1H NMR (CDCl3): 1.30 (3H, t, J = 7.3 Hz), 1.49 '(9H, s), 1.60-1.78 (2H, m), 2.81 ( 2H, m), 2.88 (2H, q, J = 7.3 Hz), 3.00-3.06 (1H, m), 4.24 (1H, m), 5.56 (1H, m ), 7.37 (1H, d, J = 8.5 Hz), 7.74 (1H, m), 7.85 (1H, dd, J = 2.4 Hz, 8.5 Hz), 7, 92 (1H, d, J = 2.4 Hz), 10.90 (1H, sa).

231  231
Rex353 ESI+: 403  Rex353 ESI +: 403

232  232
Rex353 ESI+: 392  Rex353 ESI +: 392

233  233
Rex353 ESI+: 390  Rex353 ESI +: 390

234  2. 3. 4
Rex292 RMN lH (CDCl3): 2,18 (3H, s), 2,38 (3H, s), 2,58 (4H, s.a.), 2,83 (4H, s.a.), 3,63 (2H, s.a.), 6,35 (1H, dd, J = 2,8 Hz, 8,4 Hz), 6,98 (1H, d, J = 8,4 Hz), 7,81 (1H, d, J = 2,8H), 8,66 (1H, s.a.).  Rex292 1 H NMR (CDCl3): 2.18 (3H, s), 2.38 (3H, s), 2.58 (4H, sa), 2.83 (4H, sa), 3.63 (2H, sa ), 6.35 (1H, dd, J = 2.8 Hz, 8.4 Hz), 6.98 (1H, d, J = 8.4 Hz), 7.81 (1H, d, J = 2 , 8H), 8.66 (1H, sa).

[Tabla 701[Table 701

Rex  Rex
Sin Datos  No data

235  235
Rex353 ESI+: 432  Rex353 ESI +: 432

236  236
Rex292 RMN lH (CDCl3+CD3OD): 2,42 (3H, s), 2,69 (4H, s.a.), 2,86 (4H, s.a.), 3,05 (3H, s), 6,44 (1H, dd, J = 2,8 Hz, 8,4 Hz), 6,87 (1H, d, J=2,8 Hz), 7,08 (1H, d, J = 8,8 Hz).  Rex292 1 H NMR (CDCl3 + CD3OD): 2.42 (3H, s), 2.69 (4H, sa), 2.86 (4H, sa), 3.05 (3H, s), 6.44 (1H , dd, J = 2.8 Hz, 8.4 Hz), 6.87 (1H, d, J = 2.8 Hz), 7.08 (1H, d, J = 8.8 Hz).

237  237
Rex516 RMN lH (CDCl3): 2,39 (3H, s), 2,64 (4h, s.a.), 2,97 (4H, t, J = 4,8 Hz), 3,19 (3H, s), 7,28 (1H, d, J = 8,8 Hz), 7,53 (1H, s.a.), 7,97 (1H, dd, J = 2,4 Hz, 8,4 Hz), 8,31 (1H, d, J = 2,4 Hz).  Rex516 NMR lH (CDCl3): 2.39 (3H, s), 2.64 (4h, sa), 2.97 (4H, t, J = 4.8 Hz), 3.19 (3H, s), 7.28 (1H, d, J = 8.8 Hz), 7.53 (1H, sa), 7.97 (1H, dd, J = 2.4 Hz, 8.4 Hz), 8.31 ( 1H, d, J = 2.4 Hz).

238  238
Rex353 ESI+: 468  Rex353 ESI +: 468

239  239
Rex292 RMN 1H (CDCl3): 2,35 (3H, s), 2,45 (4H, s.a.), 2,85 (4H, t, J = 4,8 Hz), 3,54 (2H, s.a.), 6,62-6,65 (2H, m), 6,92 (1H, d, J = 9,2 Hz), 7,29 (1H, t, J = 7,6 Hz), 7,36 (2H, t, J = 7,6 Hz), 7,57 (2H, d, J = 7,2 Hz).  Rex292 1H NMR (CDCl3): 2.35 (3H, s), 2.45 (4H, sa), 2.85 (4H, t, J = 4.8 Hz), 3.54 (2H, sa), 6.62-6.65 (2H, m), 6.92 (1H, d, J = 9.2 Hz), 7.29 (1H, t, J = 7.6 Hz), 7.36 (2H , t, J = 7.6 Hz), 7.57 (2H, d, J = 7.2 Hz).

240  240
Rex240 rMn iH (CDCls): 2,27 (3H, s), 2,34 (4H, s.a.), 2,99 (4H, t, J = 4,8 Hz), 7,01 (1H, d, J = 9,2 Hz), 7,35 (1H, t, J = 7,2 Hz), 7,44 (2H, t, J = 7,2 Hz), 7,58 (2H, d, J = 7,2 Hz), 8,08 (1H, d, J = 2,8 Hz), 8,14 (1H, dd, J = 2,8 Hz, 9,2 Hz).  Rex240 rMn iH (CDCls): 2.27 (3H, s), 2.34 (4H, sa), 2.99 (4H, t, J = 4.8 Hz), 7.01 (1H, d, J = 9.2 Hz), 7.35 (1H, t, J = 7.2 Hz), 7.44 (2H, t, J = 7.2 Hz), 7.58 (2H, d, J = 7 , 2 Hz), 8.08 (1H, d, J = 2.8 Hz), 8.14 (1H, dd, J = 2.8 Hz, 9.2 Hz).

241  241
Rex516 ESI+: 348  Rex516 ESI +: 348

242  242
Rex353 ESI+: 451  Rex353 ESI +: 451

243  243
Rex292 RMN lH (CDCl3): 1,91 (3H, s), 2,34 (3H, s), 2,55 (4H, s.a.), 2,87 (4H, m), 3,22 (3H, s), 3,64 (2H, s.a.), 6,47 (1H, s), 6,66 (1H, d, J = 8,8 Hz), 6,95 (1H, d, J = 8,4 Hz).  Rex292 1 H NMR (CDCl3): 1.91 (3H, s), 2.34 (3H, s), 2.55 (4H, sa), 2.87 (4H, m), 3.22 (3H, s ), 3.64 (2H, sa), 6.47 (1H, s), 6.66 (1H, d, J = 8.8 Hz), 6.95 (1H, d, J = 8.4 Hz ).

244  244
Rex244 RMN 1H (CDCl3): 1,98 (3H, s), 2,35 (3H, s), 2,56 (4H, t, J = 4,8 Hz), 3,18 (4H, dd, J = 3,6 Hz, 5,6 Hz), 3,26 (3H, s), 7,05 (1H, d, J = 9,2 Hz), 7,98 (1H, d, J = 2,4 Hz), 8,14 (1H, dd, J = 2,4 Hz, 8,8 Hz).  Rex244 1H NMR (CDCl3): 1.98 (3H, s), 2.35 (3H, s), 2.56 (4H, t, J = 4.8 Hz), 3.18 (4H, dd, J = 3.6 Hz, 5.6 Hz), 3.26 (3H, s), 7.05 (1H, d, J = 9.2 Hz), 7.98 (1H, d, J = 2.4 Hz), 8.14 (1H, dd, J = 2.4 Hz, 8.8 Hz).

5 ______________________________________[Tabla 7115 ______________________________________ [Table 711

Rex  Rex
Sin Datos  No data

245  245
Rex353 ESI+: 446  Rex353 ESI +: 446

246  246
Rex246 RMN lH (CDCl3): 0,90 (3H, t, J = 7,8 Hz), 1,40-1,55 (15H, m), 1,61-1,64 (2H, m), 1,78-1,82 (2H, m), 3,39 (1H, m), 4,42 (1H, m).  Rex246 1 H NMR (CDCl3): 0.90 (3H, t, J = 7.8 Hz), 1.40-1.55 (15H, m), 1.61-1.64 (2H, m), 1 , 78-1.82 (2H, m), 3.39 (1H, m), 4.42 (1H, m).

247  247
Rex247 RMN lH (CD3OD): 0,90 (3h, t, J = 7,6 Hz), 1,30-1,54 (6H, m), 1,62-1,65 (3H, m), 2,52-2,58 (1H, m).  Rex247 NMR lH (CD3OD): 0.90 (3h, t, J = 7.6 Hz), 1.30-1.54 (6H, m), 1.62-1.65 (3H, m), 2 , 52-2.58 (1 H, m).

248  248
Rex246 RMN lH (CDCl3): 0,91 (3H, t, J = 7,6 Hz), 1,32-1,49 (13H, m), 1,54 (2H, q, J = 7,6 Hz), 1,60-1,66 (2H, m), 1,88-1,93 (2H, m), 3,59 (1H, m), 4,55 (1H, m).  Rex246 NMR lH (CDCl3): 0.91 (3H, t, J = 7.6 Hz), 1.32-1.49 (13H, m), 1.54 (2H, q, J = 7.6 Hz ), 1.60-1.66 (2H, m), 1.88-1.93 (2H, m), 3.59 (1H, m), 4.55 (1H, m).

249  249
Rex249 rMn iH (CD3OD): 0,89 (3H, t, J = '7,6 Hz), 1,20-1,31 (2H, m), 1,38-1,45 (2H, m), 1,55 (2H, q, J = 7,6 Hz), 1,68-1,81 (4H, m), 2,70-2,75 (1H, m).  Rex249 rMn iH (CD3OD): 0.89 (3H, t, J = '7.6 Hz), 1.20-1.31 (2H, m), 1.38-1.45 (2H, m), 1.55 (2H, q, J = 7.6 Hz), 1.68-1.81 (4H, m), 2.70-2.75 (1H, m).

250  250
Rex250 rMn iH (CDCI3): 0,91 (6H, d, J = 6,8 Hz), 1,43-1,49 (11H, m), 1,51-1,63 (5H, m), 1,81-1,83 (2H, m), 3,37 (1H, m), 4,41 (1H, m).  Rex250 rMn iH (CDCI3): 0.91 (6H, d, J = 6.8 Hz), 1.43-1.49 (11H, m), 1.51-1.63 (5H, m), 1 , 81-1.83 (2H, m), 3.37 (1H, m), 4.41 (1H, m).

251  251
Rex251 RMN lH (DMSO-d6): 0,82 (6H, d, J = 6,8 Hz), 1,24-1,31 (2H, m), 1,43-1,53 (3H, m), 1,65-1,67 (4H, m), 2,85-2,89 (1H, m), 3,87 (1H, m), 7,88 (2H, m).  Rex251 NMR lH (DMSO-d6): 0.82 (6H, d, J = 6.8 Hz), 1.24-1.31 (2H, m), 1.43-1.53 (3H, m) , 1.65-1.67 (4H, m), 2.85-2.89 (1H, m), 3.87 (1H, m), 7.88 (2H, m).

252  252
Rex250 rMn iH (CDCl3): 0,92 (6H, d, J = 6,8 Hz), 1,43-1,45 (11H, m), 1,52-1,55 (2H, m), 1,64-1,76 (3H, m), 1,88-1,92 (2H, m), 3,68 (1H, m), 4,53 (1H, m).  Rex250 rMn iH (CDCl3): 0.92 (6H, d, J = 6.8 Hz), 1.43-1.45 (11H, m), 1.52-1.55 (2H, m), 1 , 64-1.76 (3H, m), 1.88-1.92 (2H, m), 3.68 (1H, m), 4.53 (1H, m).

253  253
Rex253 RMN lH (DMSO-d6): 0,83 (6H, d, J = 6,8 Hz), 1,25-1,32 (2H, m), 1,48 (2H, m), 1,62-1,68 (3H, m), 1,82-1,88 (2H, m), 3,17 (1H, m), 3,92 (1H, m), 7,84 (2H, m).  Rex253 NMR lH (DMSO-d6): 0.83 (6H, d, J = 6.8 Hz), 1.25-1.32 (2H, m), 1.48 (2H, m), 1.62 -1.68 (3H, m), 1.82-1.88 (2H, m), 3.17 (1H, m), 3.92 (1H, m), 7.84 (2H, m).

254  254
Rex353 ESI+: 453  Rex353 ESI +: 453

Rex  Rex
Sin Datos  No data

255  255
Rex292 RMN 1H (CDCl3): 1,48 (9H, s), 1,85-1,93 (2H, m), 2,23 (3H, s), 2,93-3,02 (4H, m), 3,45-3,59 (6H, m), 6,47 (1H, d, J = 8,3 Hz), 6,53 (1H, s), 6,86 (1H, d, J = 8,3 Hz).  Rex292 1H NMR (CDCl3): 1.48 (9H, s), 1.85-1.93 (2H, m), 2.23 (3H, s), 2.93-3.02 (4H, m) , 3.45-3.59 (6H, m), 6.47 (1H, d, J = 8.3 Hz), 6.53 (1H, s), 6.86 (1H, d, J = 8 , 3 Hz).

256  256
Rex353 RMN ‘H (CDCl3): 1,28 (3H, t, J = 7,3 Hz), 1,49 (9H, s), 1,91-1,96 (2H, m), 2,31 (3H, s), 2,84 (2H, q, J = 7,3 Hz), 3,00-3,08 (4H, m), 3,56-3,61 (4H, m), 5,50 (1H, s.a.), 7,01-7,04 (1H, m), 7,34 (1H, s), 7,52 (1H, m), 7,71 (1H, s.a.), 10,60 (1H, s.a.).  Rex353 NMR 'H (CDCl3): 1.28 (3H, t, J = 7.3 Hz), 1.49 (9H, s), 1.91-1.96 (2H, m), 2.31 ( 3H, s), 2.84 (2H, q, J = 7.3 Hz), 3.00-3.08 (4H, m), 3.56-3.61 (4H, m), 5.50 (1H, sa), 7.01-7.04 (1H, m), 7.34 (1H, s), 7.52 (1H, m), 7.71 (1H, sa), 10.60 ( 1H, sa).

257  257
Rex292 RMN 1H (Cd3oD): 1,49 (9H, s), 2,02-2,20 (6H, m), 2,37 (3H, s), 2,77-2,86 (2H, m), 3,27-3,34 (6H, m), 3,48-3,65 (6H, m), 3,96 (1H, t, J = 15,4 Hz), 7,18-7,23 (3H, m).  Rex292 1H NMR (Cd3oD): 1.49 (9H, s), 2.02-2.20 (6H, m), 2.37 (3H, s), 2.77-2.86 (2H, m) , 3.27-3.34 (6H, m), 3.48-3.65 (6H, m), 3.96 (1H, t, J = 15.4 Hz), 7.18-7.23 (3H, m).

258  258
Rex503 rMn 1H (CDCI3): 1,47 (9H, s), 1,69-1,90 (6H, m), 2,35 (3H, s), 2,61-2,80 (7H, m), 3,30-3,33 (2H, m), 3,42-3,50 (4H, m), 6,96 (1H, d, J = 8,3 Hz), 8,00-8,03 (2H, m).  Rex503 rMn 1H (CDCI3): 1.47 (9H, s), 1.69-1.90 (6H, m), 2.35 (3H, s), 2.61-2.80 (7H, m) , 3.30-3.33 (2H, m), 3.42-3.50 (4H, m), 6.96 (1H, d, J = 8.3 Hz), 8.00-8.03 (2H, m).

259  259
Rex516 ESI+: 235  Rex516 ESI +: 235

260  260
Rex292 RMN 1H (CDCl3): 1,63 (2H, m), 2,03-2,94 (21H, m), 3,63 (2H, s.a.), 6,34 (1H, d, J = 8,4 Hz), 6,93 (1H, d, J = 8,4 Hz), 7,81 (1H, s), 8,61 (1H, s.a.).  Rex292 1H NMR (CDCl3): 1.63 (2H, m), 2.03-2.94 (21H, m), 3.63 (2H, sa), 6.34 (1H, d, J = 8, 4 Hz), 6.93 (1H, d, J = 8.4 Hz), 7.81 (1H, s), 8.61 (1H, sa).

261  261
Rex503 RMN 1H (CDCl3): 1,64-1,73 (2H, m), 2,12 (2H, d, J = 12,8 Hz), 2,24 (3H, s), 2,29-2,38 (1H, m), 2,31 (3H, s), 2,50 (4H, s.a.), 2,66 (4H, s.a.), 2,75 (2H, t, J = 12,4 Hz), 3,15 (2H, d, J = 12,0 Hz), 7,16 (1H, d, J = 8,8 Hz), 7,92 (1H, dd, J = 2,8 Hz, 8,8 Hz), 8,07 (1H, s.a.), 9,16 (1H, d, J = 2,4 Hz).  Rex503 1H NMR (CDCl3): 1.64-1.73 (2H, m), 2.12 (2H, d, J = 12.8 Hz), 2.24 (3H, s), 2.29-2 , 38 (1H, m), 2.31 (3H, s), 2.50 (4H, sa), 2.66 (4H, sa), 2.75 (2H, t, J = 12.4 Hz) , 3.15 (2H, d, J = 12.0 Hz), 7.16 (1H, d, J = 8.8 Hz), 7.92 (1H, dd, J = 2.8 Hz, 8, 8 Hz), 8.07 (1H, sa), 9.16 (1H, d, J = 2.4 Hz).

262  262
Rex516 RMN 1H (CDCl3): 2,29 (3H, s), 2,68 (4H, t, J = 6,0 Hz), 3,27 (4H, t, J = 6,0 Hz), 7,23 (1H, d, J = 8,8 Hz), 7,97 (1H, dd, J = 2,4 Hz, 8,8 Hz), 8,16 (1H, s.a.), 9,22 (1H, s.a.).  Rex516 1H NMR (CDCl3): 2.29 (3H, s), 2.68 (4H, t, J = 6.0 Hz), 3.27 (4H, t, J = 6.0 Hz), 7, 23 (1H, d, J = 8.8 Hz), 7.97 (1H, dd, J = 2.4 Hz, 8.8 Hz), 8.16 (1H, sa), 9.22 (1H, sa).

[Tabla 731[Table 731

Rex  Rex
Sin Datos  No data

263  263
Rex353 ESI+: 515  Rex353 ESI +: 515

264  264
Rex292 RMN 1H (CDCl3): 1,63 (2H, m), 1,89 (3H, s), 1,97 (2H, m), 2,56-3,21 (19H, m), 3,61 (2H, s.a.), 6,47 (1H, d, J = 2,8 Hz), 6,61 (1H, dd, J = 2,8 Hz, 8,4 Hz), 6,91 (1H, d, J = 8,8 Hz).  Rex292 1H NMR (CDCl3): 1.63 (2H, m), 1.89 (3H, s), 1.97 (2H, m), 2.56-3.21 (19H, m), 3.61 (2H, sa), 6.47 (1H, d, J = 2.8 Hz), 6.61 (1H, dd, J = 2.8 Hz, 8.4 Hz), 6.91 (1H, d , J = 8.8 Hz).

265  265
Rex244 RMN 1H (CDCl3): 1,62 (2H, m), 1,96 (3H, s), 2,00 (2h, m),' 2,29 (3H, s), 2,36 (1H, m), 2,48 (4H, s.a.), 2,48 (4H, s.a.), 2,61 (4H, s.a.), 2,86 (4H, m), 3,48 (3H, s), 3,51 (2H, t, J = 10,8 Hz), 7,03 (1H, d, J = 9,2 Hz), 7,96 (1H, d, J = 2,8 Hz), 8,11 (1H, dd, J = 2,8 Hz, 9,2 Hz).  Rex244 1H NMR (CDCl3): 1.62 (2H, m), 1.96 (3H, s), 2.00 (2h, m), '2.29 (3H, s), 2.36 (1H, m), 2.48 (4H, sa), 2.48 (4H, sa), 2.61 (4H, sa), 2.86 (4H, m), 3.48 (3H, s), 3, 51 (2H, t, J = 10.8 Hz), 7.03 (1H, d, J = 9.2 Hz), 7.96 (1H, d, J = 2.8 Hz), 8.11 ( 1H, dd, J = 2.8 Hz, 9.2 Hz).

266  266
Rex353 ESI+: 529  Rex353 ESI +: 529

267  267
Rex292 RMN 1H (CDCl3): 0,62-0,66 (2H, m), 0,91-0,96 (2H, m), 2,35 (1H, m), 2,35 (3H, s), 2,57 (4H, s.a.), 2,96 (4H, s), 3,42 (2H, s.a.), 6,08 (1H, d, J = 2,4 Hz), 6,46 (1H, dd, J = 2,4 Hz, 8,4 Hz), 6,88 (1H, d, J = 8,4 Hz).  Rex292 1H NMR (CDCl3): 0.62-0.66 (2H, m), 0.91-0.96 (2H, m), 2.35 (1H, m), 2.35 (3H, s) , 2.57 (4H, sa), 2.96 (4H, s), 3.42 (2H, sa), 6.08 (1H, d, J = 2.4 Hz), 6.46 (1H, dd, J = 2.4 Hz, 8.4 Hz), 6.88 (1H, d, J = 8.4 Hz).

268  268
Rex240 RMN 1H (CDCl3): 0,83 (2H, m), 1,09 (2H, m), 2,15 (1H, m), 2,38 (3H, s), 2,62 (4H, s.a.), 3,21 (4H, s.a.), 6,99 (1H, d, J = 8,4 Hz), 7,68 (1H, d, J = 2,8 Hz), 7,99 (1H, dd, J = 2,4 Hz, 8,8 Hz).  Rex240 1H NMR (CDCl3): 0.83 (2H, m), 1.09 (2H, m), 2.15 (1H, m), 2.38 (3H, s), 2.62 (4H, sa ), 3.21 (4H, sa), 6.99 (1H, d, J = 8.4 Hz), 7.68 (1H, d, J = 2.8 Hz), 7.99 (1H, dd , J = 2.4 Hz, 8.8 Hz).

269  269
Rex353 ESI+: 415  Rex353 ESI +: 415

270  270
Rex292 EI :251  Rex292 EI: 251

271  271
Rex516 EI:281  Rex516 EI: 281

272  272
Rex353 ESI-: 433  Rex353 ESI-: 433

273  273
Rex353 ESI+: 482  Rex353 ESI +: 482

274  274
Rex292 RMN 1H (CD3OD): 2,54 (3H, s), 2,57 (3H, s), 2,90-2,94 (4H, m), 2,99-3,02 (4H, m), 6,80 (1H, dd, J = 2,4 Hz, 8,8 Hz), 7,09 (1H, d, J = 8,8 Hz), 7,22 (1H, d, J = 2,4 Hz).  Rex292 1H NMR (CD3OD): 2.54 (3H, s), 2.57 (3H, s), 2.90-2.94 (4H, m), 2.99-3.02 (4H, m) , 6.80 (1H, dd, J = 2.4 Hz, 8.8 Hz), 7.09 (1H, d, J = 8.8 Hz), 7.22 (1H, d, J = 2, 4 Hz)

5 ______________________________________[Tabla 7415 ______________________________________ [Table 741

Rex  Rex
Sin Datos  No data

275  275
Rex516 RMN 1H (CDCl3): 2,39 (3H, s), 2,60 (4H, m), 3,04 (3H, d, J = 4,8 Hz), 3,12-3,15 (4H, m), 7,17 (1H, d, J = 8,8 Hz), 8,23 (1H, dd, J = 2,4 Hz, 8,8 Hz), 8,80 (1H, d, J = 2,4 Hz).  Rex516 1H NMR (CDCl3): 2.39 (3H, s), 2.60 (4H, m), 3.04 (3H, d, J = 4.8 Hz), 3.12-3.15 (4H , m), 7.17 (1H, d, J = 8.8 Hz), 8.23 (1H, dd, J = 2.4 Hz, 8.8 Hz), 8.80 (1H, d, J = 2.4 Hz).

276  276
Rex353 ESI+: 432  Rex353 ESI +: 432

277  277
Rex292 RMN 1H (CD3OD): 1,69-1,71 (2H, m), 1,92-1,95 (2H, m), 2,35 (3H, s), 2,55 (3H, s), 2,57-2,82 (9H, m), 3,14 (2H, m), 3,31 (2H, m), 3,34 (6H, s), 6,86-6,88 (1H, m), 7,20-7,22 (2H, m).  Rex292 1H NMR (CD3OD): 1.69-1.71 (2H, m), 1.92-1.95 (2H, m), 2.35 (3H, s), 2.55 (3H, s) , 2.57-2.82 (9H, m), 3.14 (2H, m), 3.31 (2H, m), 3.34 (6H, s), 6.86-6.88 (1H , m), 7.20-7.22 (2H, m).

278  278
Rex503 rMn 1H (CDCla): 1,71-1,80 (2h, m),1,96-1,99 (2H, m), 2,30 (3H, s), 2,49-2,64 (9H, m), 2,80 (6H, s), 2,84 (2H, m), 3,57-3,60 (2H, m), 7,31 (1H, d, J = 9,2 Hz), 8,30 (1H, dd, J = 2,8 Hz, 9,2 Hz), 8,71 (1H, d, J = 2,8 Hz).  Rex503 rMn 1H (CDCla): 1.71-1.80 (2h, m), 1.96-1.99 (2H, m), 2.30 (3H, s), 2.49-2.64 ( 9H, m), 2.80 (6H, s), 2.84 (2H, m), 3.57-3.60 (2H, m), 7.31 (1H, d, J = 9.2 Hz ), 8.30 (1H, dd, J = 2.8 Hz, 9.2 Hz), 8.71 (1H, d, J = 2.8 Hz).

279  279
Rex516 RMN 1H (CDCl3): 2,69-2,72 (4H, m), 2,86 (6H, s), 3,47-3,50 (4H, m), 7,39 (1H, d, J = 8,8 Hz), 8,36 (1H, dd, J = 2,4 Hz, 8,8 Hz), 8,71 (1H, d, J = 2,4H).  Rex516 1H NMR (CDCl3): 2.69-2.72 (4H, m), 2.86 (6H, s), 3.47-3.50 (4H, m), 7.39 (1H, d, J = 8.8 Hz), 8.36 (1H, dd, J = 2.4 Hz, 8.8 Hz), 8.71 (1H, d, J = 2.4H).

280  280
Rex353 ESI+: 565  Rex353 ESI +: 565

281  281
Rex292 RMN 1H (CDCl3): 2,48 (3H, s), 2,98 (4H, m), 3,31 (7H, m), 6,90 (1H, dd, J = 2,8 Hz, 8,4 Hz), 7,21 (1H, d, J = 2,8 Hz), 7,27 (1 H, d, J = 8,4 Hz).  Rex292 1H NMR (CDCl3): 2.48 (3H, s), 2.98 (4H, m), 3.31 (7H, m), 6.90 (1H, dd, J = 2.8 Hz, 8 , 4 Hz), 7.21 (1H, d, J = 2.8 Hz), 7.27 (1 H, d, J = 8.4 Hz).

282  282
Rex516 EI: 328  Rex516 EI: 328

283  283
Rex353 ESI+: 468  Rex353 ESI +: 468

284  284
Rex292 RMN 1H (CDCl3): 2,88 (3H, s), 2,96 (3H, s), 3,14 (3H, s), 3,19-3,56 (8H, m), 7,09 (1H, s), 7,29 (2H, m).  Rex292 1H NMR (CDCl3): 2.88 (3H, s), 2.96 (3H, s), 3.14 (3H, s), 3.19-3.56 (8H, m), 7.09 (1H, s), 7.29 (2H, m).

285  285
Rex516 RMN 1H (CDCl3): 2,34 (3H, s), 2,49-2,51 (4H, m), 2,88 (3H, s), 3,13-3,16 (2H, m), 3,15 (3H, s), 3,38 (2H, m), 6,64 (1H, d, J = 8,8 Hz), 8,14-8,18 (2H, m).  Rex516 1H NMR (CDCl3): 2.34 (3H, s), 2.49-2.51 (4H, m), 2.88 (3H, s), 3.13-3.16 (2H, m) , 3.15 (3H, s), 3.38 (2H, m), 6.64 (1H, d, J = 8.8 Hz), 8.14-8.18 (2H, m).

Rex  Rex
Sin Datos  No data

286  286
Rex353 ESI+: 446  Rex353 ESI +: 446

287  287
Rex287 EI: 211  Rex287 EI: 211

288  288
Rex291 ESI+: 244  Rex291 ESI +: 244

289  289
Rex292 FAB+: 214  Rex292 FAB +: 214

290  290
Rex287 EI: 211  Rex287 EI: 211

291  291
Rex291 FAB+: 244  Rex291 FAB +: 244

292  292
Rex292 FAB+: 214  Rex292 FAB +: 214

293  293
Rex298 ESI+ 401  Rex298 ESI + 401

294  294
Rex299 ESI+ 383  Rex299 ESI + 383

295  295
Rex298 ESI+ 415  Rex298 ESI + 415

296  296
Rex298 ESI+ 415  Rex298 ESI + 415

297  297
Rex299 ESI+ 397  Rex299 ESI + 397

298  298
Rex298 ESI-: 371  Rex298 ESI-: 371

299  299
Rex299 ESI-: 353  Rex299 ESI-: 353

300  300
Rex298 ESI-: 371  Rex298 ESI-: 371

301  301
Rex299 ESI-: 354  Rex299 ESI-: 354

302  302
Rex299 ESI+ 397  Rex299 ESI + 397

303  303
Rex298 ESI+ 310  Rex298 ESI + 310

304  304
Rex304 ESI+ 306  Rex304 ESI + 306

305  305
Rex298 ESI+ 352  Rex298 ESI + 352

306  306
Rex299 FAB+: 334  Rex299 FAB +: 334

307  307
Rex298 ESI+ 338  Rex298 ESI + 338

308  308
Rex298 ESI+ 330,332  Rex298 ESI + 330,332

309  309
Rex298 ESI+ 366  Rex298 ESI + 366

310  310
Rex299 ESI+ 348  Rex299 ESI + 348

311  311
Rex311 FAB+: 350  Rex311 FAB +: 350

312  312
Rex299 ESI-: 318  Rex299 ESI-: 318

313  313
Rex298 ESI+ 374  Rex298 ESI + 374

314  314
Rex299 ESI+ 56  Rex299 ESI + 56

315  315
Rex298 ESI+ 387  Rex298 ESI + 387

316  316
Rex298 ESI+ 401  Rex298 ESI + 401

[Tabla 76][Table 76]

Rex  Rex
Sin Datos  No data

317  317
Rex339 ESI+: 292  Rex339 ESI +: 292

318  318
Rex304 ESI+: 326,328  Rex304 ESI +: 326,328

319  319
Rex339 ESI-: 310  Rex339 ESI-: 310

320  320
Rex299 APCI-: 367  APCI Rex299-: 367

321  321
Rex299 ESI-: 381  Rex299 ESI-: 381

322  322
Rex298 APCI-: 400  Rex298 APCI-: 400

323  323
Rex298 ESI-: 336  Rex298 ESI-: 336

324  324
Rex298 ESI+: 364  Rex298 ESI +: 364

325  325
Rex299 ESI+: 384  Rex299 ESI +: 384

326  326
Rex298 ESI+: 388  Rex298 ESI +: 388

327  327
Rex299 APCI-: 368  Rex299 APCI-: 368

328  328
Rex298 ESI+: 392  Rex298 ESI +: 392

329  329
Rex298 ESI+: 404  Rex298 ESI +: 404

330  330
Rex298 ESI+: 326  Rex298 ESI +: 326

331  331
Rex299 ESI-: 318  Rex299 ESI-: 318

332  332
Rex298 ESI+: 388  Rex298 ESI +: 388

333  333
Rex298 ESI+: 427  Rex298 ESI +: 427

334  334
Rex299 ESI-: 344  Rex299 ESI-: 344

335  335
Rex299 ESI-: 386  Rex299 ESI-: 386

336  336
Rex299 ESI-: 373  Rex299 ESI-: 373

337  337
Rex304 ESI+: 322  Rex304 ESI +: 322

338  338
Rex299 ESI-: 407  Rex299 ESI-: 407

339  339
Rex339 ESI+: 308  Rex339 ESI +: 308

340  340
Rex346 ESI+: 412  Rex346 ESI +: 412

341  341
Rex349 ESI+: 370  Rex349 ESI +: 370

342  342
Rex342 ESI+: 387, 389  Rex342 ESI +: 387, 389

343  343
Rex342 FAB+: 369  Rex342 FAB +: 369

Rex  Rex
Sin Datos  No data

344  344
Rex298 ESI+: 346  Rex298 ESI +: 346

345  3. 4. 5
Rex298 ESI+: 372  Rex298 ESI +: 372

346  346
Rex346 ESI+: 370  Rex346 ESI +: 370

347  347
Rex346 ESI+: 396  Rex346 ESI +: 396

[Tabla 771[Table 771

Rex  Rex
Sin Datos  No data

348  348
Rex349 ESI+ 354  Rex349 ESI + 354

349  349
Rex349 ESI+ 328  Rex349 ESI + 328

350  350
Rex298 ESI+ 372  Rex298 ESI + 372

351  351
Rex298 ESI+ 407, 409  Rex298 ESI + 407, 409

352  352
Rex298 ESI+ 330  Rex298 ESI + 330

353  353
Rex353 ESI+ 355  Rex353 ESI + 355

354  354
Rex299 ESI+ 389, 391  Rex299 ESI + 389, 391

355  355
Rex346 ESI+ 396  Rex346 ESI + 396

356  356
Rex298 ESI+ 330  Rex298 ESI + 330

357  357
Rex346 ESI+ 354  Rex346 ESI + 354

358  358
Rex349 ESI+ 354  Rex349 ESI + 354

359  359
Rex298 ESI+ 310, 312  Rex298 ESI + 310, 312

360  360
Rex353 ESI+ 308, 310  Rex353 ESI + 308, 310

361  361
Rex346 ESI+ 354  Rex346 ESI + 354

362  362
Rex349 ESI+ 312  Rex349 ESI + 312

363  363
Rex349 ESI+ 312  Rex349 ESI + 312

364  364
Rex364 ESI+ 292  Rex364 ESI + 292

365  365
Rex298 ESI+ 364  Rex298 ESI + 364

366  366
Rex346 ESI+ 388  Rex346 ESI + 388

367  367
Rex298 ESI+ 364  Rex298 ESI + 364

368  368
Rex346 ESI+ 388  Rex346 ESI + 388

369  369
Rex349 ESI+ 346  Rex349 ESI + 346

370  370
Rex349 ESI+ 346  Rex349 ESI + 346

371  371
Rex298 ESI+ 372  Rex298 ESI + 372

372  372
Rex346 ESI+ 396  Rex346 ESI + 396

373  373
Rex349 ESI+ 354  Rex349 ESI + 354

374  374
Rex298 ESI+ 296  Rex298 ESI + 296

375  375
Rex298 ESI+ 374  Rex298 ESI + 374

376  376
Rex298 ESI+ 330  Rex298 ESI + 330

377  377
Rex298 ESI+ 330  Rex298 ESI + 330

378  378
Rex298 ESI+ 398  Rex298 ESI + 398

5 ______ [Tabla 7815 ______ [Table 781

Rex  Rex
Sin Datos  No data

379  379
Rex353 FAB+: 327  Rex353 FAB +: 327

380  380
Rex346 ESI+: 422  Rex346 ESI +: 422

381  381
Rex346 ESI-: 396  Rex346 ESI-: 396

382  382
Rex346 ESI+ 320  Rex346 ESI + 320

383  383
Rex346 ESI+ 354  Rex346 ESI + 354

384  384
Rex346 ESI+ 354  Rex346 ESI + 354

385  385
Rex349 ESI+ 380  Rex349 ESI + 380

386  386
Rex349 ESI+ 356  Rex349 ESI + 356

387  387
Rex349 ESI+ 278  Rex349 ESI + 278

388  388
Rex349 ESI+ 312  Rex349 ESI + 312

389  389
Rex349 ESI+ 312  Rex349 ESI + 312

390  390
Rex353 ESI+ 278  Rex353 ESI + 278

391  391
Rex353 ESI+ 369, 371  Rex353 ESI + 369, 371

392  392
Rex353 ESI+ 361, 363  Rex353 ESI + 361, 363

393  393
Rex353 ESI+ 323  Rex353 ESI + 323

394  394
Rex353 ESI+ 323  Rex353 ESI + 323

395  395
Rex353 ESI+ 292  Rex353 ESI + 292

396  396
Rex397 ESI+ 355  Rex397 ESI + 355

397  397
Rex397 ESI+ 355  Rex397 ESI + 355

398  398
Rex398 ESI+ 234, 236  Rex398 ESI + 234, 236

Rex  Rex
Sin Datos  No data

399  399
Rex399 ESI+: 229  Rex399 ESI +: 229

400  400
Rex400 ESI+: 129  Rex400 ESI +: 129

401  401
Rex353 ESI+: 328  Rex353 ESI +: 328

402  402
Rex353 ESI-: 343  Rex353 ESI-: 343

403  403
Rex353 ESI+: 317  Rex353 ESI +: 317

404  404
Rex353 ESI+: 333  Rex353 ESI +: 333

405  405
Rex353 ESI+: 328  Rex353 ESI +: 328

406  406
Rex516 ESI+: 335  Rex516 ESI +: 335

407  407
Rex292 ESI+: 305  Rex292 ESI +: 305

408  408
Rex353 ESI+: 322  Rex353 ESI +: 322

409  409
Rex353 ESI+: 368  Rex353 ESI +: 368

[Tabla 791[Table 791

Rex  Rex
Sin Datos  No data

410  410
Rex353 ESI+: 348  Rex353 ESI +: 348

411  411
Rex353 ESI+: 361  Rex353 ESI +: 361

412  412
Rex412 FAB+: 335  Rex412 FAB +: 335

413  413
Rex413 ESI+: 306  Rex413 ESI +: 306

414  414
Rex353 ESI+: 375  Rex353 ESI +: 375

415  415
Rex353 ESI+: 405  Rex353 ESI +: 405

416  416
Rex353 ESI+: 405  Rex353 ESI +: 405

417  417
Rex417 ESI+: 387  Rex417 ESI +: 387

418  418
Rex353 ESI+: 458  Rex353 ESI +: 458

419  419
Rex353 ESI+: 433  Rex353 ESI +: 433

420  420
Rex353 ESI+: 375  Rex353 ESI +: 375

421  421
Rex516 ESI+: 349  Rex516 ESI +: 349

422  422
Rex292 ESI+: 319  Rex292 ESI +: 319

423  423
Rex353 ESI+: 488, 490  Rex353 ESI +: 488, 490

424  424
Rex353 ESI+: 443  Rex353 ESI +: 443

425  425
Rex353 ESI+: 460  Rex353 ESI +: 460

426  426
Rex516 ESI+: 373  Rex516 ESI +: 373

427  427
Rex353 ESI+: 405  Rex353 ESI +: 405

428  428
Rex353 ESI+: 362  Rex353 ESI +: 362

429  429
Rex353 ESI+: 360  Rex353 ESI +: 360

430  430
Rex430 EI: 256, 258  Rex430 EI: 256, 258

431  431
Rex430 EI: 270, 272  Rex430 EI: 270, 272

432  432
Rex432 ESI+: 321  Rex432 ESI +: 321

433  433
Rex432 ESI+: 335  Rex432 ESI +: 335

434  434
Rex292 ESI+: 291  Rex292 ESI +: 291

435  435
Rex292 ESI+: 305  Rex292 ESI +: 305

436  436
Rex292 ESI+: 343  Rex292 ESI +: 343

437  437
Rex353 FAB+: 489 491  Rex353 FAB +: 489 491

438  438
Rex454 ESI-: 409  Rex454 ESI-: 409

439  439
Rex353 ESI+: 405  Rex353 ESI +: 405

440  440
Rex440 ESI+: 538  Rex440 ESI +: 538

5 ______ [Tabla 8015 ______ [Table 801

Rex  Rex
Sin Datos  No data

441  441
Rex455 ESI+ 311  Rex455 ESI + 311

442  442
Rex353 ESI+ 443  Rex353 ESI + 443

443  443
Rex353 ESI+ 374  Rex353 ESI + 374

444  444
Rex444 ESI+ 252  Rex444 ESI + 252

445  445
Rex292 ESI+ 222  Rex292 ESI + 222

446  446
Rex353 ESI+ 355, 357  Rex353 ESI + 355, 357

447  447
Rex353 ESI+ 405  Rex353 ESI + 405

448  448
Rex464 ESI+ 408  Rex464 ESI + 408

449  449
Rex468 ESI+ 274  Rex468 ESI + 274

450  450
Rex353 ESI+ 457  Rex353 ESI + 457

451  451
Rex516 ESI+ 305  Rex516 ESI + 305

452  452
Rex292 ESI+ 275  Rex292 ESI + 275

453  453
Rex353 ESI+ 458  Rex353 ESI + 458

Rex  Rex
Sin Datos  No data

454  454
Rex454 ESI+ 441  Rex454 ESI + 441

455  455
Rex455 ESI+ 341  Rex455 ESI + 341

456  456
Rex516 ESI+ 290  Rex516 ESI + 290

457  457
Rex292 ESI+ 260  Rex292 ESI + 260

458  458
Rex353 ESI+ 443  Rex353 ESI + 443

459  459
Rex516 ESI+ 379  Rex516 ESI + 379

460  460
Rex292 ESI+ 349  Rex292 ESI + 349

461  461
Rex353 ESI+ 405  Rex353 ESI + 405

462  462
Rex454 ESI+ 441  Rex454 ESI + 441

463  463
Rex455 APCI/ESI+: 341  Rex455 APCI / ESI +: 341

464  464
Rex464 ESI+ 355  Rex464 ESI + 355

465  465
Rex464 ESI+ 438  Rex464 ESI + 438

466  466
Rex467 ESI+ 277  Rex467 ESI + 277

467  467
Rex467 ESI+ 291  Rex467 ESI + 291

468  468
Rex468 ESI+ 221  Rex468 ESI + 221

469  469
Rex468 ESI+ 304  Rex468 ESI + 304

470  470
Rex353 ESI+ 404, 406  Rex353 ESI + 404, 406

471  471
Rex353 ESI+ 487, 489  Rex353 ESI + 487, 489

[Tabla 811[Table 811

Rex  Rex
Sin Datos  No data

472  472
Rex472 ESI+: 275  Rex472 ESI +: 275

473  473
Rex473 APCI/ESI+: 279  Rex473 APCI / ESI +: 279

474  474
Rex292 APCI/ESI+: 249  Rex292 APCI / ESI +: 249

475  475
Rex516 APCI/ESI+: 237  Rex516 APCI / ESI +: 237

476  476
Rex353 APCI/ESI+: 432, 434  Rex353 APCI / ESI +: 432, 434

477  477
Rex292 APCI/ESI+: 207  Rex292 APCI / ESI +: 207

478  478
Rex454 FAB+: 411  Rex454 FAB +: 411

479  479
Rex455 ESI+ 311  Rex455 ESI + 311

480  480
Rex464 ESI+ 325  Rex464 ESI + 325

481  481
Rex468 ESI+ 191  Rex468 ESI + 191

482  482
Rex464 ESI+ 408  Rex464 ESI + 408

483  483
Rex464 ESI+ 438  Rex464 ESI + 438

484  484
Rex468 ESI+ 274  Rex468 ESI + 274

485  485
Rex353 ESI+ 409  Rex353 ESI + 409

486  486
Rex468 ESI+ 304  Rex468 ESI + 304

487  487
Rex353 ESI+ 404  Rex353 ESI + 404

488  488
Rex353 ESI+ 374  Rex353 ESI + 374

489  489
Rex353 ESI+ 487  Rex353 ESI + 487

490  490
Rex353 ESI+ 457  Rex353 ESI + 457

491  491
Rex353 APCI/ESI+: 390, 392  Rex353 APCI / ESI +: 390, 392

492  492
Rex502 EI:220  Rex502 EI: 220

493  493
Rex503 ESI+ 419  Rex503 ESI + 419

494  494
Rex455 ESI+ 319  Rex455 ESI + 319

495  495
Rex444 ESI+ 295  Rex444 ESI + 295

496  496
Rex464 ESI+ 333  Rex464 ESI + 333

497  497
Rex292 ESI+ 265  Rex292 ESI + 265

498  498
Rex292 ESI+ 303  Rex292 ESI + 303

499  499
Rex444 ESI+ 279  Rex444 ESI + 279

500  500
Rex353 APCI/ESI+: 486, 488  Rex353 APCI / ESI +: 486, 488

501  501
Rex353 ESI+: 420  Rex353 ESI +: 420

502  502
Rex502 APCI/ESI+: 251  Rex502 APCI / ESI +: 251

Rex  Rex
Sin Datos  No data

503  503
Rex503 APCI/ESI+: 335  Rex503 APCI / ESI +: 335

504  504
Rex292 APCI/ESI+: 305  Rex292 APCI / ESI +: 305

505  505
Rex353 APCI/ESI+: 406  Rex353 APCI / ESI +: 406

506  506
Rex353 APCI/ESI+: 433  Rex353 APCI / ESI +: 433

507  507
Rex353 APCI/ESI+: 420  Rex353 APCI / ESI +: 420

508  508
Rex353 APCI/ESI+: 419  Rex353 APCI / ESI +: 419

509  509
Rex353 APCI/ESI+: 488  Rex353 APCI / ESI +: 488

510  510
Rex502 APCI/ESI+: 235  Rex502 APCI / ESI +: 235

511  511
Rex503 APCI/ESI+: 319  Rex503 APCI / ESI +: 319

512  512
Rex292 APCI/ESI+: 239  Rex292 APCI / ESI +: 239

513  513
Rex353 ESI+: 472  Rex353 ESI +: 472

514  514
Rex432 ESI+: 308  Rex432 ESI +: 308

515  515
Rex432 ESI+: 322  Rex432 ESI +: 322

516  516
Rex516 ESI+: 279  Rex516 ESI +: 279

517  517
Rex292 ESI+: 249  Rex292 ESI +: 249

518  518
Rex516 ESI+: 295  Rex516 ESI +: 295

519  519
Rex292 APCI/ESI+: 265  Rex292 APCI / ESI +: 265

520  520
Rex353 ESI+: 404  Rex353 ESI +: 404

521  521
Rex353 ESI+: 420  Rex353 ESI +: 420

522  522
Rex292 ESI+: 292  Rex292 ESI +: 292

523  523
Rex292 ESI+: 278  Rex292 ESI +: 278

524  524
Rex353 ESI+: 475, 477  Rex353 ESI +: 475, 477

525  525
Rex353 ESI+: 488, 490  Rex353 ESI +: 488, 490

526  526
Rex353 ESI+: 502, 504  Rex353 ESI +: 502, 504

527  527
Rex353 ESI+: 474, 476  Rex353 ESI +: 474, 476

528  528
Rex353 ESI+: 474  Rex353 ESI +: 474

529  529
Rex353 ESI+: 461  Rex353 ESI +: 461

530  530
Rex467 ESI+: 278  Rex467 ESI +: 278

531  531
Rex353 ESI+: 461, 463  Rex353 ESI +: 461, 463

532  532
Rex353 ESI+: 460, 462  Rex353 ESI +: 460, 462

533  533
Rex430 EI: 270, 272  Rex430 EI: 270, 272

[Tabla 83][Table 83]

Rex  Rex
Sin Datos  No data

534  534
Rex432 ESI+ 335  Rex432 ESI + 335

535  535
Rex292 ESI+ 305  Rex292 ESI + 305

536  536
Rex353 ESI+ 488, 490  Rex353 ESI + 488, 490

537  537
Rex432 ESI+ 322  Rex432 ESI + 322

538  538
Rex292 ESI+ 292  Rex292 ESI + 292

539  539
Rex353 ESI+ 475, 477  Rex353 ESI + 475, 477

540  540
Rex353 ESI+ 532, 534  Rex353 ESI + 532, 534

541  541
Rex516 ESI+ 319  Rex516 ESI + 319

542  542
Rex292 ESI+ 289  Rex292 ESI + 289

543  543
Rex545 ESI+ 389  Rex545 ESI + 389

544  544
Rex353 ESI+ 435  Rex353 ESI + 435

545  545
Rex545 APCI/ESI+: 419  Rex545 APCI / ESI +: 419

546  546
Rex417 ESI+: 470  Rex417 ESI +: 470

547  547
Rex353 APCI/ESI+: 488  Rex353 APCI / ESI +: 488

548  548
Rex353 RMN 'H (CDCl3):1,28(3H, t, J = 7,3 Hz), 2,36(3H, S), 2,62 (4H, s.a.), 2,85 (2H, q, J = 7,6 Hz), 3,10 (4H, s.a.), 5,50(1H, s.a.), 6,91-6,99 (1H, m), 7,25 (1H, s.a.), 7,53 (1H, d, J = 14,4 Hz), 7,71 (1H, s.a.), 10,71 (1H, s.a.)  Rex353 NMR 'H (CDCl3): 1.28 (3H, t, J = 7.3 Hz), 2.36 (3H, S), 2.62 (4H, sa), 2.85 (2H, q, J = 7.6 Hz), 3.10 (4H, sa), 5.50 (1H, sa), 6.91-6.99 (1H, m), 7.25 (1H, sa), 7, 53 (1H, d, J = 14.4 Hz), 7.71 (1H, sa), 10.71 (1H, sa)

549  549
Rex353 ESI+ 506  Rex353 ESI + 506

550  550
Rex545 ESI+ 490  Rex545 ESI + 490

551  551
Rex516 ESI+ 319  Rex516 ESI + 319

552  552
Rex292 ESI+ 289  Rex292 ESI + 289

553  553
Rex353 ESI+ 472  Rex353 ESI + 472

554  554
Rex516 RMN 1H (CDCI3) :1,71-2,17 (6H, m), 2,35 (4H, m), 2,72-2,75 (4H, m), 2,99-3,02 (2H, m), 3,30-3,32 (4H, m), 6,87-6,92 (1H, m), 7,87-7,99 (2H, m)  Rex516 1H NMR (CDCI3): 1.71-2.17 (6H, m), 2.35 (4H, m), 2.72-2.75 (4H, m), 2.99-3.02 ( 2H, m), 3.30-3.32 (4H, m), 6.87-6.92 (1H, m), 7.87-7.99 (2H, m)

555  555
Rex292 ESI+: 293  Rex292 ESI +: 293

Rex  Rex
Sin Datos  No data

556  556
Rex353 RMN 'H (CDCl3): 1,26-1,32 (3H, m), 1,56-1,65 (2H, m), 1,84-1,97 (4H, m), 2,30 (4H, m), 2,72-3,09 (12H, m), 5,49 (1H, s.a.), 6,90-6,95 (1H, m), 7,17-7,29 (1H, m), 7,52-7,56 (1H, m), 7,71 (1H, s.a.), 10,71 (1H, s.a.)  Rex353 NMR 'H (CDCl3): 1.26-1.32 (3H, m), 1.56-1.65 (2H, m), 1.84-1.97 (4H, m), 2.30 (4H, m), 2.72-3.09 (12H, m), 5.49 (1H, sa), 6.90-6.95 (1H, m), 7.17-7.29 (1H , m), 7.52-7.56 (1H, m), 7.71 (1H, sa), 10.71 (1H, sa)

557  557
Rex516 RMN lH (CDCI3): 1,59 (2H, m), 1,82-1,85 (2H, m), 1,93-1,98 (2H, m), 2,27 (4H, s.a.), 2,75 (4H, t, J = 4,6 Hz), 2,91-2,94 (2H, m), 3,24-3,26 (4H, m), 3,95 (3H, s), 6,87 (1H, d, J = 9,0 Hz), 7,70 (1H, d, J = 2,4 Hz), 7,85 (1H, dd, J = 2,7, 9,0 Hz)  Rex516 NMR lH (CDCI3): 1.59 (2H, m), 1.82-1.85 (2H, m), 1.93-1.98 (2H, m), 2.27 (4H, sa) , 2.75 (4H, t, J = 4.6 Hz), 2.91-2.94 (2H, m), 3.24-3.26 (4H, m), 3.95 (3H, s ), 6.87 (1H, d, J = 9.0 Hz), 7.70 (1H, d, J = 2.4 Hz), 7.85 (1H, dd, J = 2.7, 9, 0 Hz)

558  558
Rex292 RMN 'H (CDCla): 1,65-2,00 (8H, m)/ 2,29 (4H, s.a.), 2,75-2,76 (4H, m), 2,93-3,03 (6H, m), 3,83 (3H, s), 6,23-6,26 (2H, m), 6,76 (1H, d, J = 8,1 Hz)  Rex292 NMR 'H (CDCla): 1.65-2.00 (8H, m) / 2.29 (4H, sa), 2.75-2.76 (4H, m), 2.93-3.03 (6H, m), 3.83 (3H, s), 6.23-6.26 (2H, m), 6.76 (1H, d, J = 8.1 Hz)

559  559
Rex353 RMN ‘H (CDCls): 1,57-1,98 (11H, m), 2,29 (5H, m), 2,78 (4H, s.a.), 2,94-2,96 (2H, m), 3,09 (4H, s.a.), 3,71 (1H, s.a.), 3,90 (3H, s), 5,56 (1H, s.a.), 6,91 (1H, d, J = 8,5H), 7,13 (1H, dd, J = 2,4, 8,5 Hz), 7,36 (1H, d, J = 2,4 Hz), 7,41 (1H, s.a.), 10,76 (1H, s.a.)  Rex353 NMR 'H (CDCls): 1.57-1.98 (11H, m), 2.29 (5H, m), 2.78 (4H, sa), 2.94-2.96 (2H, m ), 3.09 (4H, sa), 3.71 (1H, sa), 3.90 (3H, s), 5.56 (1H, sa), 6.91 (1H, d, J = 8, 5H), 7.13 (1H, dd, J = 2.4, 8.5 Hz), 7.36 (1H, d, J = 2.4 Hz), 7.41 (1H, sa), 10, 76 (1H, sa)

560  560
Rex545 ESI+: 502  Rex545 ESI +: 502

561  561
Rex353 ESI+: 423  Rex353 ESI +: 423

562  562
Rex545 RMN ’H (CDCl3): 1,26 (6H, d, J = 6,8 Hz), 2,37 (3H, S), 2,62 (4H, s.a.), 3,10 (4H, s.a.), 3,40-3,47 (1H, m), 5,52 (1H, s.a.), 6,91-6,96 (1H, m), 7,24-7,26 (1H, m), 7,53 (1H, dd, J = 2,7, 14,6 Hz), 7,69 (1H, s.a.), 10,70 (1H, s.a.)  Rex545 NMR 'H (CDCl3): 1.26 (6H, d, J = 6.8 Hz), 2.37 (3H, S), 2.62 (4H, sa), 3.10 (4H, sa) , 3.40-3.47 (1H, m), 5.52 (1H, sa), 6.91-6.96 (1H, m), 7.24-7.26 (1H, m), 7 , 53 (1H, dd, J = 2.7, 14.6 Hz), 7.69 (1H, sa), 10.70 (1H, sa)

[Tabla 851 (# no es parte de la invencion)[Table 851 (# is not part of the invention)

Ej  Ex
Estructura  Structure

1#  one#
NH2 o S'VV'n'V*’; o=^=o ^ ^ Me Me iPr  NH2 or S'VV'n'V * ’; o = ^ = o ^ ^ Me Me iPr

2#  2#
Nh2 n Yr o=l-o" H o iPr  Nh2 n Yr o = l-o "H or iPr

3#  3#
nrr y=oH H O iPr  nrr y = oH H O iPr

4#  4#
NH2 o=f=oH H Q iPr  NH2 o = f = oH H Q iPr

5#  5#
f^O yfVr VA'NANAN'><JMe= °t°h h Q iPr U  f ^ O yfVr VA'NANAN '> <JMe = ° t ° h h Q iPr U

6#  6 #
o^\ JL II NH V>AV><NM8* 4°h H Q iPr &  o ^ \ JL II NH V> AV> <NM8 * 4 ° h H Q iPr &

Ej  Ex
Estructura  Structure

7#  7 #
Vh2q r^Y^H V1"n'^n^'n'^xnh2 0=s=0 ^ H Me Me iPr  Vh2q r ^ Y ^ H V1 "n '^ n ^' n '^ xnh2 0 = s = 0 ^ H Me Me iPr

8#  8 #
nh2 oX V iii li NH 0=^=0H H O iPr  nh2 oX V iii li NH 0 = ^ = 0H H O iPr

9#  9 #
nh2 ^o=\ X Yr VVvV^ o=foH H() jpr \---/  nh2 ^ o = \ X Yr VVvV ^ o = foH H () jpr \ --- /

10#  10 #
nh2 ril li NH fi 0=^=0H H OH iPr  nh2 ril li NH fi 0 = ^ = 0H H OH iPr

11#  eleven#
To mV CT°H 0^=0H H iPr  To mV CT ° H 0 ^ = 0H H iPr

12#  12 #
nh2 d iXy'nh rY"2 0=^=0H H iPr  nh2 d iXy'nh rY "2 0 = ^ = 0H H iPr

13#  13 #
nh2o ffSrW X'r'NH2 V'Yn^n""^ 0=^=0H H iPr  nh2o ffSrW X'r'NH2 V'Yn ^ n "" ^ 0 = ^ = 0H H iPr

JLJL

imagen107image107

15#fifteen#

EstructuraStructure

16#16 #

imagen108image108

17#17 #

18#18 #

19#19 #

imagen109image109

imagen110image110

JLJL

imagen111image111

29#29 #

EstructuraStructure

30#30 #

imagen112image112

31#31 #

imagen113image113

32#32 #

33#33 #

imagen114image114

Ej  Ex
Estructura  Structure

34#  3. 4#
NH2 “vtSpnh H H0  NH2 “vtSpnh H H0

35#  35 #
nh2G o XTS r us' *0 h h r^j  nh2G or XTS r us' * 0 h h r ^ j

36#  36 #
NH2 ^0=1 X r ll H NH h2nvXAnAn^n0<nh2 4 H H Q  NH2 ^ 0 = 1 X r ll H NH h2nvXAnAn ^ n0 <nh2 4 H H Q

37#  37 #
NH2Q aXCCx,-^  NH2Q aXCCx, - ^

38#  38 #
nh2q „ oX, X Ml ll NH 4 H H Q  nh2q „oX, X Ml ll NH 4 H H Q

39#  39 #
NH2 q o rfjr ^ Me Xd H H | 1  NH2 q or rfjr ^ Me Xd H H | one

40#  40 #
nh2 -^JdX X 111 Ji INH >X^N'J-N^NXXNMe2 Me vo ^ H C j  nh2 - ^ JdX X 111 Ji INH> X ^ N'J-N ^ NXXNMe2 Me vo ^ H C j

[0334]  [0334]
(# no es parte de la invencion)  (# is not part of the invention)

Ej  Ex
Estructura  Structure

41#  41 #
NH2 0 o H nH ^cr  NH2 0 or H nH ^ cr

42#  42 #
NH, Q ' l NH h2n 'o H H Q  NH, Q 'l NH h2n' or H H Q

43#  43 #
0 T2ff [j NH ^=^n-JVJ'n'><nh* H H0  0 T2ff [j NH ^ = ^ n-JVJ'n '> <nh * H H0

44#  44 #
jJHz0 q ni°Vr ,pr "b h h 0  jJHz0 q ni ° Vr, pr "b h h 0

45#  Four. Five#
5% o rii Y^NH )s^^rr'N^N'ANH2 Et 'b H H Q  5% o rii Y ^ NH) s ^^ rr'N ^ N'ANH2 Et 'b H H Q

46#  46 #
NH2 0 q f'f'f'T Me2N nn0 H H [ ]  NH2 0 q f'f'f'T Me2N nn0 H H []

47#  47 #
Cl nh n^nAn*V><!"° H  Cl nh n ^ nAn * V> <! "° H

Ej  Ex
Estructura  Structure

48#  48 #
P° o 1r H 0 H H Q  P ° o 1st H 0 H H Q

49#  49 #
NH2q f-^o=y^NH I » "0  NH2q f- ^ o = y ^ NH I »" 0

50#  fifty#
CF NH2° ry° ii NH I " "0  CF NH2 ° r and ° ii NH I "" 0

51#  51 #
T*o _ 0=\ 1 /~~i iii Y^nh o H H Q  T * o _ 0 = \ 1 / ~~ i iii Y ^ nh or H H Q

52#  52 #
NH2 0 X o nrr ^ N0 H H Q  NH2 0 X or nrr ^ N0 H H Q

53#  53 #
Nh2q Me0YrY'^ n^nX^nAn^><nh2 H H0  Nh2q Me0YrY '^ n ^ nX ^ nAn ^> <nh2 H H0

54#  54 #
NH, pnortrr H H0  NH, pnortrr H H0

imagen115image115

Ej  Ex
Estructura  Structure

62#  62 #
NH2 ° \ 9 o H H 0  NH2 ° \ 9 or H H 0

63#  63 #
NH2 1L1 >~v. ffil jTiJ 1 H H NH,  NH2 1L1> ~ v. ffil jTiJ 1 H H NH,

64#  64 #
nh2 o r^^V^NH r^i 040^0000 W ^ H H NH,  nh2 or r ^^ V ^ NH r ^ i 040 ^ 0000 W ^ H H NH,

65#  65 #
nh2 Me>rVSlY^n Hci-^^n-^'n^-n'><nh2 H HQ  nh2 Me> rVSlY ^ n Hci - ^^ n - ^ 'n ^ -n'> <nh2 H HQ

66#  66 #
n NH= E^N r^T]| 1yH  n NH = E ^ N r ^ T] | 1yH

67#  67 #
00 Nh2 Ty° li NH *0/n'An0“> H H0  00 Nh2 Ty ° li NH * 0 / n'An0 “> H H0

68#  68 #
NH2 0 Ph -~.0:=\ JL 01 W n*A00n->0 H H0  NH2 0 Ph - ~ .0: = \ JL 01 W n * A00n-> 0 H H0

Ej  Ex
Estructura  Structure

69#  69 #
T29 "VfYr H H  T29 "VfYr H H

70#  70 #
"vfYV N^xN'^'N^N'^/lPr H H  "vfYV N ^ xN '^' N ^ N '^ / lPr H H

71#  71 #
nh2 Ph0W "\inh N N N H H  nh2 Ph0W "\ inh N N N H H

72#  72 #
7H=o Ph0W ii nh ^ N N N ^ 2 H H  7H = o Ph0W ii nh ^ N N N ^ 2 H H

73#  73 #
NH2 ,«ccoo ^ H H NH,  NH2, "ccoo ^ H H NH,

74#  74 #
jh2 8. H H0  jh2 8. H H0

75#  75 #
m2 % H H Q  m2% H H Q

imagen116image116

[Tabla 97  [Table 97
(# no es parte de la invencion)  (# is not part of the invention)

Ej  Ex
Estructura  Structure

83#  83 #
0 2 0 Me.. '/ 0=^ jf n' Fl) YXH ci^J1'nJ-nAm-><nh3 H H0  0 2 0 Me .. '/ 0 = ^ jf n' Fl) YXH ci ^ J1'nJ-nAm -> <nh3 H H0

84#  84 #
nh2 □ A°TYB Me ^ H H f]  nh2 □ A ° TYB Me ^ H H f]

85#  85 #
nh2 ^XXlTO Me-S '-^'N N N" A b H H NH,  nh2 ^ XXlTO Me-S '- ^' N N N "A b H H NH,

86#  86 #
Nh2 oX^IAEI ^\>0H XXIX lj  Nh2 oX ^ IAEI ^ \> 0H XXIX lj

87#  87 #
NH2 q X hh n0nAnAnA<NH2 ph h h Q  NH2 q X hh n0nAnAnA <NH2 ph h h Q

88#  88 #
nh2o A°T*  nh2o A ° T *

89#  89 #
nh2 MeO Et H H0  nh2 MeO Et H H0

Ej  Ex
Estructura  Structure

90#  90 #
Me jlH2o M1°V''nh H HQ  I jlH2o M1 ° V''nh H HQ

91#  91 #
NH, XN1XXXx jO H H nh2  NH, XN1XXXx jO H H nh2

92#  92 #
ff JX Et2N o'XtXr X MeO^fj NAN/r H H NH,  ff JX Et2N o'XtXr X MeO ^ fj NAN / r H H NH,

93#  93 #
O jJH20 rXrx0 y> rx H H NH,  Or jJH20 rXrx0 and> rx H H NH,

94#  94 #
CD Y  CD Y

95#  95 #
0 _jH20 iPr Ji /s. 0:=\ 11 n'y^ tX nh ri H X1 A y X J H H NH,  0 _jH20 iPr Ji / s. 0: = \ 11 n'y ^ tX nh ri H X1 A and X J H H NH,

96#  96 #
NH, g ■ F. \ JL h YX Y> rX |pr^ Y N N YY 6 H H NH,  NH, g ■ F. \ JL h YX Y> rX | pr ^ Y N N YY 6 H H NH,

97#  97 #
NH F .^OA X. ooaXxo & H H NH,  NH F. ^ OA X. ooaXxo & H H NH,

Ej  Ex
Estructura  Structure

98#  98 #
NHjq Vf YNH r^"'| O H H NH?  NHjq Vf YNH r ^ "'| O H H NH?

99#  99 #
NH2 © K X IT O Et2NYJ^ANAN^r/vJ O H H NH?  NH2 © K X IT O Et2NYJ ^ ANAN ^ r / vJ O H H NH?

100#  100 #
NH2Q i H hQ  NH2Q i H hQ

101#  101 #
nh2 Me ^ H H  nh2 Me ^ H H

102#  102 #
NH2 o r^° yVEt Me^ No H H f J  NH2 or r ^ ° yVEt Me ^ No H H f J

103#  103 #
nh2 ^O^ylvyEt °'s^nAA>c°h Me H H [ J  nh2 ^ O ^ ylvyEt ° 's ^ nAA> c ° h Me H H [J

104#  104 #
nh2 Q F*vf”Sinh  nh2 Q F * vf ”Sinh

Ej  Ex
Estructura  Structure

105#  105 #
Cl VH2 0 1 o=\ Q f\\ li NH nY^'n'^n^n'><nh^ Cl H H Q HCI  Cl VH2 0 1 o = \ Q f \\ li NH nY ^ 'n' ^ n ^ n '> <nh ^ Cl H H Q HCI

106#  106 #
nh2 VirVlO^ fh H H Q  nh2 VirVlO ^ fh H H Q

107#  107 #
Nh2q n ^0"Si NH r"YOH Me ^ h H  Nh2q n ^ 0 "Yes NH r" YOH Me ^ h H

108#  108 #
nh2 o nTfY'ryMe . ^S^NN' N ^ Me H H  nh2 or nTfY'ryMe. ^ S ^ NN 'N ^ Me H H

109#  109 #
NH, 0 X Jl I X S. TMe fTN PT^  NH, 0 X Jl I X S. TMe fTN PT ^

110#  110 #
_yNHj oh ^,oYn ,Et ^PH q f 1 IT [ rMe u iA7 Me 'q H H  _yNHj oh ^, oYn, Et ^ PH q f 1 IT [rMe u iA7 Me 'q H H

111#  111 #
nh2 Me H H  nh2 Me H H

112#  112 #
NH, Me ^ H H  NH, Me ^ H H

Ej  Ex
Estructura  Structure

113#  113 #
Br ^h20 n°| f N^AN'^N^N'><N^  Br ^ h20 n ° | f N ^ AN '^ N ^ N'> <N ^

114#  114 #
Nhj Q JL f\\ f| NH H  Nhj Q JL f \\ f | NH H

115#  115 #
Cl j^O II NH WvVx^ H H0  Cl j ^ O II NH WvVx ^ H H0

116#  116 #
a VH=o rjTVx nh ^ANANAN"X = H  a VH = o rjTVx nh ^ ANANAN "X = H

117#  117 #
Br ,nh2Q ry0H H H  Br, nh2Q ry0H H H

118#  118 #
IPr, j? r=9 ^rtrxx) H H NH,  IPr, j? r = 9 ^ rtrxx) H H NH,

119#  119 #
nh2 a ffjQCJ^JO ^ % H H NH,  nh2 to ffjQCJ ^ JO ^% H H NH,

[Tabla 102  [Table 102
(# no es parte de la invencion)  (# is not part of the invention)

Ej  Ex
Estructura  Structure

120#  120 #
0 nh2o rrVfrr Me^'''N^N^N^NH=  0 nh2o rrVfrr Me ^ '' 'N ^ N ^ N ^ NH =

121#  121 #
XWXnh HMe^'-N^-N^-N^NH=  XWXnh HMe ^ '- N ^ -N ^ -N ^ NH =

122#  122 #
H H NH?  H H NH?

123#  123 #
T2ff oDcww 0 H H NH,  T2ff oDcww 0 H H NH,

124#  124 #
jWCw2 4 H H NH,  jWCw2 4 H H NH,

125#  125 #
3 H H NH,  3 H H NH,

126#  126 #
T29 ..b^cOxo S H H NH,  T29 ..b ^ cOxo S H H NH,

Ej  Ex
Estructura  Structure

127#  127 #
T20 00 F00]V^NH S H H Q  T20 00 F00] V ^ NH S H H Q

128#  128 #
0 J0O Me'NVfY'NH F C N N N >< l ^ H H [ 1  0 J0O Me'NVfY'NH F C N N N> <l ^ H H [1

129#  129 #
nh2 0 \ X o AirF W 00X000^, ^ % H H 0  nh2 0 \ X or AirF W 00X000 ^, ^% H H 0

130#  130 #
Bo To Me"N0t^-.O^\0 J XVA , ,~,,A Meo'^B N ’  Bo To Me "N0t ^ -. O ^ \ 0 J XVA,, ~ ,, A Meo '^ B N’

131#  131 #
HO Nh2 n i ° aAm-A. Am/^NH2 Me° f! N H 0  HO Nh2 n ° aAm-A. Am / ^ NH2 Me ° f! N H 0

132#  132 #
0 ^2 n i^N^Y^^Y^NH 00 ^ Me^'0^N^'Vv H H NH,  0 ^ 2 n i ^ N ^ Y ^^ Y ^ NH 00 ^ Me ^ '0 ^ N ^' Vv H H NH,

133#  133 #
O NH2Q Me'N\0°:V'NH 00 H JL1 X A X J H H NH,  OR NH2Q Me'N \ 0 °: V'NH 00 H JL1 X A X J H H NH,

Ej  Ex
Estructura  Structure

134#  134 #
9 ,nh2 o e^°Ynh Me° H h p ^  9, nh2 or e ^ ° Ynh Me ° H h p ^

135#  135 #
^ fl T2? ti nh «•<> H N  ^ fl T2? ti nh «• <> H N

136#  136 #
0 VH2 0 Me~N"IYI° ll NH  0 VH2 0 Me ~ N "IYI ° ll NH

137#  137 #
o fto YN IYi° ll NH Y-1 /kJsJL Am^^nh2 MeO fj N  o fto YN IYi ° ll NH Y-1 / kJsJL Am ^^ nh2 MeO fj N

138#  138 #
NH2Q nMen°^NH I H HQ  NH2Q nMen ° ^ NH I H HQ

139#  139 #
Me. ^<yK JL H YT Y>H -V^irYY  I. ^ <yK JL H YT Y> H -V ^ irYY

140#  140 #
o To kN n rNH YF 3 H H [ ]  o To kN n rNH YF 3 H H []

Ej  Ex
Estructura  Structure

141#  141 #
NH2 q h Fn°Yr m iPr.Nr^NAN^C><NH2 A H H Q  NH2 q h Fn ° Yr m iPr.Nr ^ NAN ^ C> <NH2 A H H Q

142#  142 #
NH2n H Yfrr o H h r j  NH2n H Yfrr or H h r j

143#  143 #
NH, g I « "Q  NH, g I «" Q

144#  144 #
NH2 q Fv ^vp=\ X Yii ii NH Et?N.. A,J-.nAnX.n^_NH? A H H Q  NH2 q Fv ^ vp = \ X Yii ii NH Et? N .. A, J-.nAnX.n ^ _NH? A H H Q

145#  145 #
CF, NHS„ Cl^ri|0|i fih H  CF, NHS „Cl ^ ri | 0 | i fih H

146#  146 #
p NH2 Me';y^'s..pXr-N^ ,Et /^oh  p NH2 Me '; and ^' s..pXr-N ^, Et / ^ oh

147#  147 #
Nhtj r^VirV5' n iajl X X xx°» A ^ NNN Me ^ H H  Nhtj r ^ VirV5 'n iajl X X xx ° »A ^ NNN Me ^ H H

148#  148 #
nh2 n ,Et ^v,»OMe o | 1 IT T |T Me.nAiANANAN,XJ H H  nh2 n, Et ^ v, »OMe o | 1 IT T | T Me.nAiANANAN, XJ H H

imagen117image117

Ej  Ex
Estructura  Structure

157#  157 #
Me-Sr^NAN^N''^ O H H  Me-Sr ^ NAN ^ N '' ^ O H H

158#  158 #
nh2 s rtffrT' ip'Y'^  nh2 s rtffrT 'ip'Y' ^

159#  159 #
/xyOH No H H  / xyOH No H H

160#  160 #
Me'N^V^° r ^VEt r^T"0H li.fi H H  Me'N ^ V ^ ° r ^ VEt r ^ T "0H li.fi H H

161#  161 #
o NH2 ^nV^^V0 /'•v*oh 3 H H  o NH2 ^ nV ^^ V0 / '• v * oh 3 H H

162#  162 #
NH2 OH W^Et /-.^OH 0 Me H H  NH2 OH W ^ Et /-.^OH 0 Me H H

163#  163 #
0 NH2 r'>"OH H H  0 NH2 r '> "OH H H

164#  164 #
NH2 0< -N,. ,Et r IJ H H  NH2 0 <-N ,. , Et r IJ H H

165#  165 #
{? ^ Me~s v ^ 0< ,N.,. .Et >OH H H  {? ^ Me ~ s v ^ 0 <, N.,. .Et> OH H H

Ej  Ex
Estructura  Structure

166#  166 #
"b H H oh  "b H H oh

167#  167 #
nh2  nh2

168#  168 #
0> ft o ri vVEt rvV* 'b H H  0> ft or ri vVEt rvV * 'b H H

169#  169 #
nh2 rf i VEt xAc 1( 3r:;s^N^N'^N-A^J Me \'G H H  nh2 rf i VEt xAc 1 (3r:; s ^ N ^ N '^ N-A ^ J Me \' G H H

170#  170 #
nh2 oY .N.. .nPr^JCSH b H H  nh2 oY .N .. .nPr ^ JCSH b H H

171#  171 #
nh2 ^^yNyEt yv^OH Me X H N h  nh2 ^^ yNyEt yv ^ OH Me X H N h

172#  172 #
nh2 0=tyN^Et /^,vOH n JL 1 <>L J O Cl H H  nh2 0 = tyN ^ Et / ^, vOH n JL 1 <> L J O Cl H H

173#  173 #
C /1° Tl NH H hO  C / 1 ° Tl NH H hO

imagen118image118

imagen119image119

Ej  Ex
Estructura  Structure

192#  192 #
Me NH2 H H  Me NH2 H H

193#  193 #
nh2 o=s=oH H Me  nh2 o = s = oH H Me

194#  194 #
"Ar^Y'fy0" H H  "Ar ^ Y'fy0" H H

195#  195 #
nh2 »xm"0" Me nn0 H H  nh2 »xm" 0 "Me nn0 H H

196#  196 #
nh2 0 [ I [ If [1 w A, A A X A ,n Me h H Me  nh2 0 [I [If [1 w A, A A X A, n Me h H Me

197#  197 #
Nh2 A>0=vVEt XA o r n [ i \ 1 w A, X A A A xi „ At Me H H  Nh2 A> 0 = vVEt XA or r n [i \ 1 w A, X A A A xi „At Me H H

198#  198 #
nh2 q, rtYfrf \\ J-is. J-L As. A A. J Me A H H  nh2 q, rtYfrf \\ J-is. J-L As. A A. J Me A H H

199#  199 #
NH2 q fYrr*rYpr Me H H  NH2 q fYrr * rYpr Me H H

Ej  Ex
Estructura  Structure

200#  200#
nh2 Me ';0 H H  nh2 Me '; 0 H H

201#  201 #
NH, jkOXcn. Me ^ H H  NH, jkOXcn. Me ^ H H

202#  202 #
nh2  nh2

203#  203 #
,nh3 Me Me o A°rrErr Me^ H H Me  , nh3 Me Me or A ° rrErr Me ^ H H Me

204#  204 #
nh2 o OE' Me^ H H  nh2 or OE 'Me ^ H H

205#  205 #
NH2 o [] XT \ T .. V^iA V1^ Me A0 H H  NH2 or [] XT \ T .. V ^ iA V1 ^ Me A0 H H

206#  206 #
NH2 0=(ij Et /v. .0 q n xt r t %A^MA.AhJv^NH n ji—-—S. N N Jvr Me ^ H H  NH2 0 = (ij Et / v. .0 q n xt r t% A ^ MA.AhJv ^ NH n ji —-— S. N N Jvr Me ^ H H

207#  207 #
nh2 ^O^N^Et o r n T IT ;s^''NANAN"cHex Me ko h H  nh2 ^ O ^ N ^ Et or r n T IT; s ^ '' NANAN "cHex Me ko h H

Ej  Ex
Estructura  Structure

208#  208 #
^0=VVEt °'Xi xi ,0 Me n). H H 1 u T)H  ^ 0 = VVEt ° 'Xi xi, 0 Me n). H H 1 u T) H

209#  209 #
nh2 O f | TT [ ] . .e j's Me H Hi 0 ''OH  nh2 O f | TT []. .e j's Me H Hi 0 '' OH

210#  210 #
nh2 r^^0=VNV'Et r^Y^5V'OMe >IJ-nX^nXX^ Me H H  nh2 r ^^ 0 = VNV'Et r ^ Y ^ 5V'OMe> IJ-nX ^ nXX ^ Me H H

211#  211 #
nh2 WKjVlvEt %XI XI JXNH  nh2 WKjVlvEt% XI XI JXNH

212#  212 #
nh2 O rn°VYEtr^ % XL X X ,CNH ^.S' ^ 'N N N' Me ^ H H  nh2 O rn ° VYEtr ^% XL X X, CNH ^ .S '^' N N N 'Me ^ H H

213#  213 #
^Hz Me .^oYX^Et a| Me ^ H H  ^ Hz Me. ^ OYX ^ Et a | Me ^ H H

214#  214 #
NH, D __/ 2 Bn .. XXXNXNXN,oX/ Me ^ H H  NH, D __ / 2 Bn .. XXXNXNXN, oX / Me ^ H H

215#  215 #
NH, D 2 Bn ^o4yNyE1 n/  NH, D 2 Bn ^ o4yNyE1 n /

Ej  Ex
Estructura  Structure

216#  216 #
nh2 Et Me' No H H NH,  nh2 Et Me 'No H H NH,

217#  217 #
nh2 si jCX XIX) Me^\ H h! o </"nh2  nh2 yes jCX XIX) Me ^ \ H h! or </ "nh2

218#  218 #
nh2 f^yyb ° (X-0H  nh2 f ^ yyb ° (X-0H

219#  219 #
nh2 ^°VyeiA ^XXXIP Me 'O H H kOH  nh2 ^ ° VyeiA ^ XXXIP Me 'O H H kOH

220#  220 #
NH2 OX VVEt rS °* XIXI x> Me ^ H H OH  NH2 OX VVEt rS ° * XIXI x> Me ^ H H OH

221#  221 #
nh2 %fXXX^ Me ^ H H  nh2% fXXX ^ Me ^ H H

222#  222 #
nh2 Ei ^XXXI^ M^vni N Oh  nh2 Ei ^ XXXI ^ M ^ vni N Oh

Ej  Ex
Estructura  Structure

223#  223 #
nh2 q f 1 I T Me 'o H Kn Mr  nh2 q f 1 I T Me 'or H Kn Mr

224#  224 #
nh2 o An \AJVs, Vvs Me H H [1  nh2 or An \ AJVs, Vvs Me H H [1

225#  225 #
nh2 ^C=Lu £t oil [ || Me "b H H Me  nh2 ^ C = Lu £ t oil [|| Me "b H H Me

226#  226 #
Nh2 w>=VVEt off T|[ Me"b H H (U  Nh2 w> = VVEt off T | [Me "b H H (U

227#  227 #
NhH2 rr0 \M.V'<><oh Me ^ H H | | XvT 1 Me  NhH2 rr0 \ M.V '<> <oh Me ^ H H | | XvT 1 Me

228#  228 #
^°=OvEt q f 1 | T Me ^ H H XA-.  ^ ° = OvEt q f 1 | T Me ^ H H XA-.

229#  229 #
Nh2 q r fl I T Me b H H li Rn  Nh2 q r fl I T Me b H H li Rn

Ej  Ex
Estructura  Structure

230#  230 #
nh2 3 ri°TrB V « ^ (PQnh  nh2 3 ri ° TrB V «^ (PQnh

231#  231 #
q ^0=OjyEt Me 'q H H [___J  q ^ 0 = OjyEt Me 'q H H [___J

232#  232 #
NHL y°<^NyEt ...... Me H H 1 J  NHL and ° <^ NyEt ...... Me H H 1 J

233#  233 #
nh2 ^0=yNyEt “^o B 'vTQO  nh2 ^ 0 = yNyEt “^ o B 'vTQO

234#  2. 3. 4#
nh2 Et O II [II Me vb H H hn[J  nh2 Et O II [II Me vb H H hn [J

235#  235 #
nh2 o rfYrEt Me \'0 H H [*)  nh2 or rfYrEt Me \ '0 H H [*)

236#  236 #
HH} o n° rrEt '0 H H ki  HH} or n ° rrEt '0 H H ki

237#  237 #
nh2 yxO=AM Et Me i H H I I u ''o  nh2 yxO = AM Et Me i H H I I u '' or

Ej  Ex
Estructura  Structure

238#  238 #
nh2 Me \\ H H 1 1 0  nh2 Me \\ H H 1 1 0

239#  239 #
NH2 pfy r T Me^ H H 1 1  NH2 pfy r T Me ^ H H 1 1

240#  240 #
NH2 Me b H H kJ Et'  NH2 Me b H H kJ Et '

241#  241 #
nh2 o f X Y T Me xo H H li-J Ft'  nh2 or f X Y T Me xo H H li-J Ft '

242#  242 #
nh2 Et o [ [ T , )s^A'N'SjAn^yS Me ^ H H 1__/  nh2 Et o [[T,) s ^ A'N'SjAn ^ yS Me ^ H H 1 __ /

243#  243 #
NH2 Y0VYEt o | fl [T b'^'N'^N'JsN'V°\ Me \N^ H H 1__/  NH2 Y0VYEt o | fl [T b '^' N '^ N'JsN'V ° \ Me \ N ^ H H 1 __ /

244#  244 #
nh2 0. [ 1 i if Me ^ H H l-NH  nh2 0. [1 i if Me ^ H H l-NH

245#  245 #
NH2 r^0=VVEt \'WvWH Me nq H H /i  NH2 r ^ 0 = VVEt \ 'WvWH Me nq H H / i

Ej  Ex
Estructura  Structure

246#  246 #
NH2 Me vq H H  NH2 Me vq H H

247#  247 #
nh2 oh ^0=VVEt J ^XX XX X N^cHex Me so H H  nh2 oh ^ 0 = VVEt J ^ XX XX X N ^ cHex Me so H H

248#  248 #
nh2 o n°rYa n >AVvV'-N-J Me" v'o H H  nh2 o n ° rYa n> AVvV'-N-J Me "v'o H H

249#  249 #
NHa o rn0=Wa r^'1* Me vo H H  NHa or rn0 = Wa r ^ '1 * Me vo H H

250#  250 #
o aXye' aoh Me vq H H  or aXye 'aoh Me vq H H

251#  251 #
nh2 ^rfri6' n 's'^/VNAhlAN/^A^ Me H H  nh2 ^ rfri6 'n' s' ^ / VNAhlAN / ^ A ^ Me H H

252#  252 #
nh2 rWXVEt rA ^ XXL X X Me A H H  nh2 rWXVEt rA ^ XXL X X Me A H H

253#  253 #
nh2 V^^n'VXt^'S Me" xb H H Me  nh2 V ^^ n'VXt ^ 'S Me "xb H H Me

Ej  Ex
Estructura  Structure

254#  254 #
nh2 o n°rrEt Me 'n H H  nh2 o n ° rrEt Me 'n H H

255#  255 #
nh2 ^Ti° r ifEt Me H H  nh2 ^ Ti ° r ifEt Me H H

256#  256 #
nH2 ^°Vyb VCO^Xr-A, -S, ^ N N N Me Me '■q H H  nH2 ^ ° Vyb VCO ^ Xr-A, -S, ^ N N N Me Me '■ q H H

257#  257 #
nh2 ^°=yiyEt Me '■o H H  nh2 ^ ° = yiyEt Me '■ or H H

258#  258 #
nh2 o rn°VrEt Me ^ h H 2  nh2 or rn ° VrEt Me ^ h H 2

259#  259 #
nh3 ^°=VNVEt.. Me H H  nh3 ^ ° = VNVEt .. Me H H

260#  260 #
NH2 ^P=k^i Et \XXaX^4 ,S, ^ N N N Ac Me 'o H H  NH2 ^ P = k ^ i Et \ XXaX ^ 4, S, ^ N N N Ac Me 'or H H

261#  261 #
nh2 o n°VrEt ? >C^N^An''~'^NH2 Me *o H H 2  nh2 or n ° VrEt? > C ^ N ^ An '' ~ '^ NH2 Me * or H H 2

Ej  Ex
Estructura  Structure

262#  262 #
Jh2 Me' No H H  Jh2 Me 'No H H

263#  263 #
nh2 o ff nEt Me H H  nh2 or ff nEt Me H H

264#  264 #
NH, Me nq H H  NH, Me nq H H

265#  265 #
nh2 ^oOCO^h Me ^ h H  nh2 ^ oOCO ^ h Me ^ h H

266#  266 #
nh2 X-OOv^y* Me ^ H H 1 ° OH  nh2 X-OOv ^ y * Me ^ H H 1 ° OH

267#  267 #
nh2 o nTV  nh2 or nTV

268#  268 #
nh2 Me ^ H H  nh2 Me ^ H H

269#  269 #
nh2 .i^Ccc, 'o H kl Me  nh2 .i ^ Ccc, 'or H kl Me

[Tabla 121  [Table 121
(# no es parte de la invencion)  (# is not part of the invention)

Ej  Ex
Estructura  Structure

270#  270 #
nh2 E\ o r 1 r T Me ^ H Uuph  nh2 E \ o r 1 r T Me ^ H Uuph

271#  271 #
« N o  " No

272#  272 #
nh2 o, nix"  nh2 o, nix "

273#  273 #
nh2 Et 0*sXJkuXN\^.me2 Me' *o H ^  nh2 Et 0 * sXJkuXN \ ^. me2 Me '* or H ^

274#  274 #
a°Y yEt °h Me "0 H 1 u Me  a ° Y yEt ° h Me "0 H 1 u Me

275#  275 #
^ oXjsl, .Et ,OMe M jXW Me H H  ^ oXjsl, .Et, OMe M jXW Me H H

276#  276 #
3 AoJ?xE,r?  3 AoJ? XE, r?

277#  277 #
nh2 Me ^ H H  nh2 Me ^ H H

Ej  Ex
Estructura  Structure

278#  278 #
nh2 Mev^YvYT'i 0  nh2 Mev ^ YvYT'i 0

279#  279 #
J™2 Me" ^ H H J,  J ™ 2 Me "^ H H J,

280#  280 #
o r TEt Me ^ H 1 1 __ i XX HO-" ^"F  or r TEt Me ^ H 1 1 __ i XX HO- "^" F

281#  281 #
MesN'Vll0 vVEt H II}] N N"^i H OH  MesN'Vll0 vVEt H II}] N N "^ i H OH

282# *  282 # *
Q NH2 M%iCwCrNVEt h jr JL I J JL joh H H  Q NH2 M% iCwCrNVEt h jr JL I J JL joh H H

283#  283 #
nh2 oC-VEt r^"'01"1 H H  nh2 oC-VEt r ^ "'01" 1 H H

284#  284 #
M6"N^ JgH* k^Nv^^O=< M^,Et ^ ,.OH 1 . H H OMe  M6 "N ^ JgH * k ^ Nv ^^ O = <M ^, Et ^, .OH 1. H H OMe

285#  285 #
Mev 9 NH2 N-S_.^ 0^ m .Et /\,>vOH H °'XX I c X)' Me/vTJ H H  Mev 9 NH2 N-S _. ^ 0 ^ m. Et / \,> vOH H ° 'XX I c X)' Me / vTJ H H

imagen120image120

[Tabla 124  [Table 124
(# no es parte de la invencion)  (# is not part of the invention)

Ej  Ex
Estructura  Structure

295#  295 #
^ ff nh2 oh O JVx0Sr'VEt rX I j] [1 ] J TMe f3c^k ^ ^  ^ ff nh2 oh O JVx0Sr'VEt rX I j] [1] J TMe f3c ^ k ^ ^

296#  296 #
^\0<' N.vviPr /NyOH 9vXl IX XX Me ^ H h  ^ \ 0 <'N. vviPr / NyOH 9vXl IX XX Me ^ H h

297#  297 #
nh2 x\>NMe2 Me ^ H H  nh2 x \> NMe2 Me ^ H H

298#  298 #
=\JlsL/Et (/'v^>OH H H  = \ JlsL / Et (/ 'v ^> OH H H

299#  299 #
NH2 ^xxix 5^01 N^NMe, Me ^ H 2  NH2 ^ xxix 5 ^ 01 N ^ NMe, Me ^ H 2

300#  300 #
Me ^ H L_/  Me ^ H L_ /

301# *  301 # *
NH? <^oX^l^nPr/'J^e 9, XIXX XXNHj Me-S^N^N^N^  NH? <^ oX ^ l ^ nPr / 'J ^ e 9, XIXX XXNHj Me-S ^ N ^ N ^ N ^

302# *  302 # *
n Me ^\0V^^W'nPrr/^NC Q [ 1 IT f r^Me, ^ <zK. J 2 Sf'^'N N N ^ Me ^ H H  n Me ^ \ 0V ^^ W'nPrr / ^ NC Q [1 IT f r ^ Me, ^ <zK. J 2 Sf '^' N N N ^ Me ^ H H

303#  303 #
a nh2 J^O==S^Nv,Et ^vy»OH H H  a nh2 J ^ O == S ^ Nv, Et ^ vy »OH H H

imagen121image121

imagen122image122

imagen123image123

imagen124image124

Ej  Ex
Estructura  Structure

339#  339 #
NH2 1 H H OMe  NH2 1 H H OMe

340  340
NH2 L^N^^OK^N^-Et ^yOH MeO'^/k'N'A'N^N"'^^ H H  NH2 L ^ N ^^ OK ^ N ^ -Et ^ yOH MeO '^ / k'N'A'N ^ N "' ^^ H H

341  341
Me.N^ ^—Nyy nh2 0^, -N^Et xvyOH H H  Me.N ^ ^ —Nyy nh2 0 ^, -N ^ Et xvyOH H H

342#  342 #
Me"N'^, NH2 H2C H H  Me "N '^, NH2 H2C H H

343  343
NH2 0=<y W,jPr y^>OH H H  NH2 0 = <and W, jPr y ^> OH H H

344#  344 #
Boc'-N-y nh2 k^N,.y. oK.n. yy0H H H  Boc'-N-y nh2 k ^ N, .y. oK.n. yy0H H H

345#  3. 4. 5#
Boc-N-y nh2 k^Nx^^=yN;;:XI r^-Y»0H fvT  Boc-N-y nh2 k ^ Nx ^^ = yN ;;: XI r ^ -Y »0H fvT

346  346
«n oT’ 1v^0Vya ^-0H wx-c H H  «N oT’ 1v ^ 0Vya ^ -0H wx-c H H

imagen125image125

imagen126image126

Ej  Ex
Estructura  Structure

361#  361 #
LX X XK JCxMe H H  LX X XK JCxMe H H

362  362
M6''N'^i NH, >Et ^JpH X Jl JI JL JL XMe H H  M6''N '^ i NH,> Et ^ JpH X Jl JI JL JL XMe H H

363#  363 #
Me ^ ^nT^i J*h> .N; .EI ^., ,,OH H H  Me ^ ^ nT ^ i J * h> .N; .EI ^., ,, OH H H

364#  364 #
W^rW® "vWita H H N J  W ^ rW® "vWita H H N J

365#  365 #
Me''N'^i NH2 k^Nv^O=(,ri.Et ^\^OH N^'NANA^ H H  Me''N '^ i NH2 k ^ Nv ^ O = (, ri.Et ^ \ ^ OH N ^' NANA ^ H H

366#  366 #
Me-N'^1 NH, fY* H H N  Me-N '^ 1 NH, fY * H H N

367#  367 #
Me"N'^1 NH2 k^N^^0=V,N^Et /vlV(OH H H  Me "N '^ 1 NH2 k ^ N ^^ 0 = V, N ^ Et / vlV (OH H H

Ej  Ex
Estructura  Structure

368#  368 #
-U^IA-U H H  -U ^ IA-U H H

369#  369 #
Me'-N'^ NH2 k^-^^ok^Et H H [1 \  Me'-N '^ NH2 k ^ - ^^ ok ^ Et H H [1 \

370  370
M6-N^ k^y^ NHj -Et /yOH FC'^'N'^N^N 3 H H  M6-N ^ k ^ and ^ NHj -Et / yOH FC '^' N '^ N ^ N 3 H H

371#  371 #
kX^ nh2 /-y OH Sj^N^N^r'T'^ H H  kX ^ nh2 / -y OH Sj ^ N ^ N ^ r'T '^ H H

372#  372 #
Me.^ k^NyA nh2 ^^vkvYEt H H [1 A  Me. ^ K ^ NyA nh2 ^^ vkvYEt H H [1 A

373#  373 #
Me-/P kx-Nyy nH2 '' tsr ' n'' i H H OMr  Me- / P kx-Nyy nH2 '' tsr 'n' 'i H H OMr

374#  374 #
<C^N^fN°=C'k^Et ^kPH XX11 X>e ^NNrT^ H H  <C ^ N ^ fN ° = C'k ^ Et ^ kPH XX11 X> e ^ NNrT ^ H H

Ej  Ex
Estructura  Structure

375  375
PH LI I I 1 rMe H H  PH LI I I 1 rMe H H

376#  376 #
M6"N^ NHj LAvv4^°=V-N^Et XX X X lxMe H H  M6 "N ^ NHj LAvv4 ^ ° = V-N ^ Et XX X X lxMe H H

377  377
We''M^\ NR, yN.,^Et H H  We''M ^ \ NR, and N., ^ Et H H

378  378
Me-Np kAp. nH2 XvXyVE' ^. ,OH H H  Me-Np kAp. nH2 XvXyVE '^. , OH H H

379#  379 #
nh2 ^WrV0 nXLmA,X,.^_^ H H [1 JL  nh2 ^ WrV0 nXLmA, X,. ^ _ ^ H H [1 JL

380#  380 #
Pi n=X 0=( w.Et ,„OH H H  Pi n = X 0 = (w.Et, „OH H H

381  381
hnA LAHy p^oH H H  hnA LAHy p ^ oH H H

382#  382 #
Boc-Np nh2 LX->^0=V'V-Et ^ .OH XIIX L X MeO^'^N^'N^N '^ H H  Boc-Np nh2 LX -> ^ 0 = V'V-Et ^ .OH XIIX L X MeO ^ '^ N ^' N ^ N '^ H H

Ej  Ex
Estructura  Structure

383#  383 #
NHZ MeO.^^O=\w Et N J H H  NHZ MeO. ^^ O = \ w Et N J H H

384#  384 #
cf3 nh2 N J H H  cf3 nh2 N J H H

385#  385 #
Me-N^ k^N-Y^N nh2 h3c 3 H H  Me-N ^ k ^ N-Y ^ N nh2 h3c 3 H H

386#  386 #
Me ^ k^NY^i T2 F,C^">^N^N^N'''''^J 3 H H  Me ^ k ^ NY ^ i T2 F, C ^ "> ^ N ^ N ^ N '' '' '^ J 3 H H

387  387
Mev ^ .... N -i NH2 N Et .»OH ^X'N'A'N^N'"k^ H H  Mev ^ .... N -i NH2 N Et. »OH ^ X'N'A'N ^ N '" k ^ H H

388  388
Vs! nh2 M\^°VNVipr /\>OH XXIX Xj F-C^^N N N 3 H H  Vs! nh2 M \ ^ ° VNVipr / \> OH XXIX Xj F-C ^^ N N N 3 H H

389  389
M6'-N^ k^Ny^ nh2 Pr _/\>NMe2 FX'^^N^NrN'N'''1^J 3 H H  M6'-N ^ k ^ Ny ^ nh2 Pr _ / \> NMe2 FX '^^ N ^ NrN'N' '' 1 ^ J 3 H H

Ej  Ex
Estructura  Structure

390  390
OH H H  OH H H

391  391
T jl fl 1 { Jp"Me H H  T jl fl 1 {Jp "Me H H

392  392
k^N.^o=<M Et XI XXX/Me H H  k ^ N. ^ o = <M Et XI XXX / Me H H

393#  393 #
Boc'-N—| nh2 H N H  Boc'-N— | nh2 H N H

394  394
"O n =fH2 ^YtlcYrr H N H  "O n = fH2 ^ YtlcYrr H N H

395#  395 #
NH2 k/N0=/ m Et H H  NH2 k / N0 = / m Et H H

396  396
O-^ JH2 r l'VEt r^‘"0H rk"" H H  O- ^ JH2 r l'VEt r ^ ‘" 0H rk "" H H

397  397
F nh2 F kXXNyB^Qn 3 H H  F nh2 F kXXNyB ^ Qn 3 H H

Ej  Ex
Estructura  Structure

398#  398 #
nh2 H H  nh2 H H

399#  399 #
cPr/"'M'^" ,NH2 1 VEt F3C'^ixN^N^N^J 3 H H  cPr / "'M' ^", NH2 1 VEt F3C '^ ixN ^ N ^ N ^ J 3 H H

400#  400 #
,NH2 x6xo” H H  , NH2 x6x or "H H

401#  401 #
OMe ,NH2 mvcr N J H H  OMe, NH2 mvcr N J H H

402  402
H H  H H

403#  403 #
nh2 joTkY'Cf0” J J H H rV^ Me"Nx^  nh2 joTkY'Cf0 ”J J H H rV ^ Me" Nx ^

404#  404 #
nh2 rfixfrccr ji J H H  nh2 rfixfrccr ji J H H

405#  405 #
AC-N^ NH2 °XKmr H H  AC-N ^ NH2 ° XKmr H H

Ej  Ex
Estructura  Structure

406#  406 #
Me2N A) nh2 V-N^O=<^Et ,„OH F3c'j^I-N n"  Me2N A) nh2 V-N ^ O = <^ Et, „OH F3c'j ^ I-N n"

407  407
J™* v-Nyx0 yNYEt r'-'-r'OH F,CA^N'VS/'^ 3 H H  J ™ * v-Nyx0 yNYEt r '-'- r'OH F, CA ^ N'VS /' ^ 3 H H

408  408
Me HN^ NH2 Me^NA° iY*A"oh  Me HN ^ NH2 Me ^ NA ° iY * A "oh

409  409
Me Me''N'^| NH2 ue<l^NYxiYjTt™ f3c^n  Me''N '^ | NH2 eu <l ^ NYxiYjTt ™ f3c ^ n

410#  410 #
^Me 0 N' t*, rA^°yNv-Et ,-\V3H S^N'''SsT'N 1 H H OMfi  ^ Me 0 N 't *, rA ^ ° and NV-Et, - \ V3H S ^ N' '' SsT'N 1 H H OMfi

411#  411 #
Me''N'^ OMe ^ „0H H H  Me''N '^ OMe ^ „0H H H

412#  412 #
Me'vN'^| R—OMe /-\.,,OH H H  Me'vN '^ | R — OMe /-\.,,OH H H

Ej  Ex
Estructura  Structure

413#  413 #
r^N-^V^°=VrV'Et f^r"OH Me"N"^ r-T H H  r ^ N- ^ V ^ ° = VrV'Et f ^ r "OH Me" N "^ r-T H H

414#  414 #
MevN'^x| NH2 ,*OH H H  MevN '^ x | NH2, * OH H H

415#  415 #
O j"2 k^N^^OK>i.Et H H  O j "2 k ^ N ^^ OK> i.Et H H

416  416
iPKN^ NH2 CNv^°K.IVEt /v,„OH H H  iPKN ^ NH2 CNv ^ ° K.IVEt / v, „OH H H

417  417
Cl k^Ns^^OK^NL^Et H H  Cl k ^ Ns ^^ OK ^ NL ^ Et H H

418#  418 #
Boc'h^] nh2 k^N^ °K_N^ ,Et /\.,OH f3c-^^n^n^n^J  Boc'h ^] nh2 k ^ N ^ ° K_N ^, Et /\.,OH f3c - ^^ n ^ n ^ n ^ J

419  419
hO aJ"2 k^Nv^^0=(yN^Et 3 H H  hO aJ "2 k ^ Nv ^^ 0 = (yN ^ Et 3 H H

420#  420 #
Boc-n-'"1 mz Me^^N^N  Boc-n - '"1 mz Me ^^ N ^ N

Ej  Ex
Estructura  Structure

421  421
HN^ ,NH2 rNVE1 |^N-"0H H H  HN ^, NH2 rNVE1 | ^ N- "0H H H

422  422
Me. Me rS _/NH= 3 H H  I. Me rS _ / NH = 3 H H

423#  423 #
CHeX"N^ NH2 k/Ny\° yVEt r^i"''0H 3 H H  CHeX "N ^ NH2 k / Ny \ ° yVEt r ^ i" '' 0H 3 H H

424#  424 #
cHex ^ NH3 L^n^jvO=( n Ft ,.,oh H H  cHex ^ NH3 L ^ n ^ jvO = (n Ft,., oh H H

425  425
NH2 3 H H  NH2 3 H H

426  426
iPr"N^ ^H2 H H  iPr "N ^ ^ H2 H H

427#  427 #
Me"N^ J "9' cpr u'=^n^n^n<Lx^ H H  Me "N ^ J" 9 'cpr u' = ^ n ^ n ^ n <Lx ^ H H

428#  428 #
o H y Me'-N'^| N-0 ^,„OH H H  or H and Me'-N '^ | N-0 ^, „OH H H

Ej  Ex
Estructura  Structure

429  429
GU, nh2 ° .N_ Et .OH F3cA^'NANAN^  GU, nh2 ° .N_ Et .OH F3cA ^ 'NANAN ^

430#  430 #
ft FH2 rr0H M<TNvJ 0 r li II I ] J H H  ft FH2 rr0H M <TNvJ 0 r li II I] J H H

431#  431 #
cHex'N^ nh2 H N H  cHex'N ^ nh2 H N H

432#  432 #
B0CxN-^| NH2 O^y Et yy,OH Me-^^N Nr  B0CxN- ^ | NH2 O ^ and Et yy, OH Me - ^^ N Nr

433  433
VlHa kAyy0=yNyEt yy.,,OH H H  VlHa kAyy0 = yNyEt yy. ,, OH H H

434#  434 #
Me-,'-'0 NH2 yy.Et yy,,OH H H  Me -, '-' 0 NH2 yy.Et yy ,, OH H H

435  435
Me"N^ m2 o ^Yin0rT“  Me "N ^ m2 or ^ Yin0rT"

436 *6  436 * 6
Me"N^ NH3 o AfTiYkj 1* 3 H H  Me "N ^ NH3 or AfTiYkj 1 * 3 H H

Ej  Ex
Estructura  Structure

437 *6  437 * 6
Me"N'^1 NH2 0 TYEt  Me "N '^ 1 NH2 0 TYEt

438 *7  438 * 7
JgH2 HN"YJ f3c^/n^  JgH2 HN "YJ f3c ^ / n ^

439 *7  439 * 7
Me"N^ J^HS HN-^J yy^0 F,C'^^N'A'N^N 3 H H  Me "N ^ J ^ HS HN- ^ J yy ^ 0 F, C '^^ N'A'N ^ N 3 H H

440#  440 #
Nl-f2 _riYiE,a0H j H H Mfi" ^  Nl-f2 _riYiE, a0H j H H Mfi "^

441#  441 #
r^V^^N^N^N'' JlJ h h Mft''  r ^ V ^^ N ^ N ^ N '' JlJ h h Mft ''

442#  442 #
Cl yNH2 XoY N-Et /^y»OH rNAiANANAN'"k-J N J H H Me' ^  Cl yNH2 XoY N-Et / ^ y »OH rNAiANANAN '" k-J N J H H Me' ^

443  443
N ] ^H2 YriYcr H H  N] ^ H2 YriYcr H H

Ej  Ex
Estructura  Structure

444  444
-^.OH Me K" N ' H H  - ^. OH Me K "N 'H H

445#  445 #
yN^Et H H 1 J ^^OMe  yN ^ Et H H 1 J ^^ OMe

446  446
Me"N^ NH2 ^nY^1° k"N"Bn 3 H H  Me "N ^ NH2 ^ nY ^ 1 ° k" N "Bn 3 H H

447#  447 #
_/H2 k^N-v^^°K_N5-Et /\^OH 3 H H  _ / H2 k ^ N-v ^^ ° K_N5-Et / \ ^ OH 3 H H

448  448
Me Me>l^ NH2 0=yil,Et „*OH Me kk^KiA-A.-kJ p J N N f'T F^C h H  Me Me> l ^ NH2 0 = yil, Et „* OH Me kk ^ KiA-A.-kJ p J N N f'T F ^ C h H

449#  449 #
Me. ,Me IjH (y H 1 k/N^r. 0=yt^Et ^OH F.C'^^N^N^NT'''^ 3 H H  I. , Me IjH (and H 1 k / N ^ r. 0 = yt ^ Et ^ OH F.C '^^ N ^ N ^ NT' '' ^ 3 H H

450#  450 #
Boc"n^ NH2 kky^°K^N^Et „OH Me'A:s^N^N^xN-^/J H H  Boc "n ^ NH2 kky ^ ° K ^ N ^ Et„ OH Me'A: s ^ N ^ N ^ xN - ^ / J H H

imagen127image127

Ej  Ex
Estructura  Structure

458#  458 #
nh2 ^ 0K.N_.Et i H H Me  nh2 ^ 0K.N_.Et i H H Me

459  459
Me.N^ J*"2 XXIX Xj EtO^^N^N N’ H H  Me.N ^ J * "2 XXIX Xj EtO ^^ N ^ N N’ H H

460  460
Me"'N^x nh2 '’^YiW'r* F,C ^-^"N ^'N^'N 3 H H  Me "'N ^ x nh2'’ ^ YiW'r * F, C ^ - ^ "N ^ 'N ^' N 3 H H

461#  461 #
Me"N^> Cl /IH2 KNyk^0 yNwEt H H  Me "N ^> Cl / IH2 KNyk ^ 0 yNwEt H H

462  462
Me^N'^v| NH2 * /-N-Ac  Me ^ N '^ v | NH2 * / -N-Ac

463  463
Me"N^ NH2 0 =YNTEtjTn Vl H H  Me "N ^ NH2 0 = YNTEtjTn Vl H H

464#  464 #
Me. £ N-^ NH2 0=4.|^,Et ,OH 3 H H  I. £ N- ^ NH2 0 = 4. | ^, Et, OH 3 H H

Ej  Ex
Estructura  Structure

465#  465 #
NH2 3 H H  NH2 3 H H

466  466
Oys nh, n X 1 I I f XMe H H  Oys nh, n X 1 I I f XMe H H

467#  467 #
B0C'N'""'1 nh2 k^N'y^0=yN^yEt /-...OH H H  B0C'N '""' 1 nh2 k ^ N'y ^ 0 = yN ^ yEt /-...OH H H

468  468
HN^ NH2 N■'y^''-P^y"Et MeO'A;^N^N^rfN^ H H  HN ^ NH2 N ■ 'y ^' '- P ^ y "Et MeO'A; ^ N ^ N ^ rfN ^ H H

469  469
iPr-N^ NH2 ^^y^0=ylXyEt ^'yOH H H  iPr-N ^ NH2 ^^ y ^ 0 = ylXyEt ^ 'yOH H H

470#  470 #
cHex-N--*\ nh2 H H  cHex-N - * \ nh2 H H

471#  471 #
cu kxJv^0=yN^Et ,OH H H  cu kxJv ^ 0 = yN ^ Et, OH H H

472#  472 #
l yy,.°H H H  l yy, ° H H H

imagen128image128

Ej  Ex
Estructura  Structure

481#  481 #
,NH2 rXWjy O-^J H H ^C)  , NH2 rXWjy O- ^ J H H ^ C)

482#  482 #
nh2 MeO..^ 0-VN .C! rXiXW H H  nh2 MeO .. ^ 0-VN .C! rXiXW H H

483#  483 #
nh2 ^°=CN_.Et kl/j H H 1 Mfi  nh2 ^ ° = CN_.Et kl / j H H 1 Mfi

484#  484 #
nh2 k^N^O=yM Et ^OH H H H  nh2 k ^ N ^ O = yM Et ^ OH H H H

485#  485 #
J"2 VNroYlO'OH O H H H  J "2 VNroYlO'OH O H H H

486#  486 #
Me""N-"~'vi NHj ^Nv^OKi^w.Et ,„OH H H  I "" N- "~ 'saw NHj ^ Nv ^ OKi ^ w.Et,„ OH H H

487#  487 #
Mes-N^ NH2 l^xOxcr 1 H H Ac  Month-N ^ NH2 l ^ xOxcr 1 H H Ac

Ej  Ex
Estructura  Structure

488  488
NH2 H H  NH2 H H

489#  489 #
cHex"N^1 NH? yN, ,Et OH H H  cHex "N ^ 1 NH? and N,, Et OH H H

490 *8  490 * 8
Me"N-^ R ^NYXYVEt r> H H  I "N- ^ R ^ NYXYVEt r> H H

491 *8  491 * 8
k^N-y^ NH2 m X\IXX>H Me N N N ^ H H  k ^ N-y ^ NH2 m X \ IXX> H Me N N N ^ H H

492  492
r< yV-Et  r <yV-Et

493 *9  493 * 9
nh? Uk^O-T L Et iPr H H  nh? Uk ^ O-T L Et iPr H H

494 *9  494 * 9
Me.^ NHj /^JPr Me’^^N H H  Me. ^ NHj / ^ JPr Me ’^^ N H H

Ej  Ex
Estructura  Structure

495#  495 #
nh2 MeO^^O—wN,^C 1 /'x^OH JJ H H  nh2 MeO ^^ O — wN, ^ C 1 / 'x ^ OH JJ H H

496#  496 #
Me-r^__ N,,Et ,-^ JDH kO'^A'N'^N^N'"k-^ H H  Me-r ^ __ N ,, Et, - ^ JDH kO '^ A'N' ^ N ^ N '"k- ^ H H

497#  497 #
f^le 0 ^1 H OyNy^ O^N Ft !^V0H H H  f ^ le 0 ^ 1 H OyNy ^ O ^ N Ft! ^ V0H H H

498#  498 #
0 N H H  0 N H H

499#  499 #
nh2 MeO^OK ,N_CI N^ '>T ' N'"'""-^ I J H H rV^  nh2 MeO ^ OK, N_CI N ^ '> T' N '"'" "- ^ I J H H rV ^

500#  500 #
O', S j,H. 1 rW cNniNx a H H  O ', S j, H. 1 rW cNniNx to H H

Ej  Ex
Estructura  Structure

501#  501 #
NH2 p niYo”  NH2 for children ”

502#  502 #
NH2 rrtYcr <kJ h h  NH2 rrtYcr <kJ h h

503#  503 #
nh2 J * 1 H H  nh2 J * 1 H H

504#  504 #
nh2 n°VrEt rrOH H H  nh2 n ° VrEt rrOH H H

505#  505 #
>2 MeO^Y^Et rXwjy H H  > 2 MeO ^ Y ^ Et rXwjy H H

506#  506 #
nh2 Me.^4 m Et P'YOH 1 J H H rV^  nh2 Me. ^ 4 m Et P'YOH 1 J H H rV ^

507  507
Me ^ ^nYY YH2 =VrVEt rrBn H H  Me ^ ^ nYY YH2 = VrVEt rrBn H H

Ej  Ex
Estructura  Structure

508#  508 #
NH2 Me' 'No H H  NH2 Me '' No H H

509#  509 #
iyie ft ^ JH, H H  iyie ft ^ JH, H H

510#  510 #
nh2 , y, E t ^-^OH CT ' N N hT' N \ H H ry m.'n^  nh2, y, E t ^ - ^ OH CT 'N N hT' N \ H H ry m.'n ^

511#  511 #
nh2 r'°v^0==lvN-v'Et r^v'OH 1 H H r^V  nh2 r '° v ^ 0 == lvN-v'Et r ^ v'OH 1 H H r ^ V

512  512
Me. ^ 07H= ^nyAi ifV6* r^? Me'^5s^N^N^N'A^ H H  I. ^ 07H = ^ nyAi ifV6 * r ^? I '^ 5s ^ N ^ N ^ N'A ^ H H

513#  513 #
Me.N^ MeO^ XX.nAnXn.LJ H H  Me.N ^ MeO ^ XX.nAnXn.LJ H H

Ej  Ex
Estructura  Structure

514  514
Me"N'"‘X| NH2 3 H H  Me "N '" ‘X | NH2 3 H H

515#  515 #
iyie C V /NH2 _J\0=VN^Et /v,«OH SfXX&O Me xq H H  iyie C V / NH2 _J \ 0 = VN ^ Et / v, «OH SfXX & O Me xq H H

516#  516 #
Boc, N^Et /\(iOH H H  Boc, N ^ Et / \ (iOH H H

517#  517 #
BoCv, _,NH* 0=<_N,Et H H  BoCv, _, NH * 0 = <_ N, Et H H

518  518
HP \_/nY^i ^h2 L/NyAl11 yN^El /\ ,OH H H  HP \ _ / nY ^ i ^ h2 L / NyAl11 yN ^ El / \, OH H H

519#  519 #
Mpl nh2 l-^NY;;N0^r'rVEt 1bXi^* o  Mpl nh2 l- ^ NY ;; N0 ^ r'rVEt 1bXi ^ * o

Ej  Ex
Estructura  Structure

520#  520 #
NH2 xjiiY a o  NH2 xjiiY to o

521#  521 #
nh2 ^N->^°=dVNv-Et „>OH H H H  nh2 ^ N -> ^ ° = dVNv-Et „> OH H H H

522#  522 #
Me"N"\ kxNy^yyE, y\,,OH Me.NJUlNANANXJ L H H  Me "N" \ kxNy ^ yyE, and \ ,, OH Me.NJUlNANANXJ L H H

523#  523 #
NH2 ^Nv^°r'NV'Et r^>"0H H H  NH2 ^ Nv ^ ° r'NV'Et r ^> "0H H H

524#  524 #
1 S^Et n'"OH 'w H H  1 S ^ Et n '"OH' w H H

525#  525 #
Me"N'y NH2 \xXXXJD Me2r\T H N H  Me "N'y NH2 \ xXXXJD Me2r \ T H N H

526#  526 #
Me-N"y JJH2 k^N^^O=\.iyxEt Me o H H  Me-N "and JJH2 k ^ N ^^ O = \. IyxEt Me or H H

JLJL

imagen129image129

528#528 #

EstructuraStructure

529#529 #

imagen130image130

530#530 #

imagen131image131

531#531 #

imagen132image132

532#532 #

imagen133image133

imagen134image134

533#533 #

Ej  Ex
Estructura  Structure

534  534
Me-N^ NH2 Til i Y*CT H H  Me-N ^ NH2 Til i Y * CT H H

535  535
nh2 ^^v^0=VNV'Et r^V0 Jk 1111 1 Me N N N ^ Me H H  nh2 ^^ v ^ 0 = VNV'Et r ^ V0 Jk 1111 1 Me N N N ^ Me H H

536#  536 #
Oy-\ jn Va M h-T" N H H  Oy- \ jn Va M h-T "N H H

537#  537 #
Vl /NH2 oH^n^ci /-^>oh MeO'^^N'^N^N '""""^ H H  Vl / NH2 oH ^ n ^ ci / - ^> oh MeO '^^ N' ^ N ^ N '"" "" ^ H H

538  538
Me^N^ 1^nY^| nh2 H H  Me ^ N ^ 1 ^ nY ^ | nh2 H H

539  539
Me--N'^''| k/N^ nH, k^v^^0 V^V"01 /^y.OH H H  Me - N '^' '| k / N ^ nH, k ^ v ^^ 0 V ^ V "01 /^y.OH H H

540#  540 #
k-Nyv, ^2 k/N^O=( m Et ^yNxnh H H  k-Nyv, ^ 2 k / N ^ O = (m Et ^ yNxnh H H

imagen135image135

EJ  Ej
ESTRUCTURA  STRUCTURE

548  548
“SPS 0 /Nq MeO'^^^N nT^N H H  “SPS 0 / Nq MeO '^^^ N nT ^ N H H

549  549
Me-^ 0 ^mVp,r0 H H  Me- ^ 0 ^ mVp, r0 H H

550  550
°ni5Y:iX? H H  ° ni5Y: iX? H H

551  551
N ^ L. i _ N 'l u M 0 ^ViVtV0 MeO''-'^-''' '■NAN^NA-^ H H  N ^ L. i _ N 'l u M 0 ^ ViVtV0 MeO' '-' ^ - '' '' ■ NAN ^ NA- ^ H H

552  552
Me>^ w M 0 k,N^lN^N Et .,- 0 N ^ N H H  Me> ^ w M 0 k, N ^ lN ^ N Et., - 0 N ^ N H H

553  553
Me'N"'N 0 WTrYV0 MeOM A N H H  Me'N "'N 0 WTrYV0 MeOM A N H H

EJ  Ej
ESTRUCTURA  STRUCTURE

554  554
Me"N^ 0 1 J. HJSiui .. ^ Yu Y V f"° H H  Me "N ^ 0 1 J. HJSiui .. ^ Yu Y V f" ° H H

555  555
Me-v. I ^ H Nji /iPrp0 H H  Me-v. I ^ H Nji / iPrp0 H H

556  556
Me.N- 0 O^N<rNYiPrr.0 MeO NNT' N H H  Me.N- 0 O ^ N <rNYiPrr. 0 MeO NNT 'N H H

557  557
Me"N^ WJ^jvr? H H  I "N ^ WJ ^ jvr? H H

558  558
Me"N^ [x^'N'^xi 0 t ' H N fi Me-^^ N^fT" N'^N-/I H H  Me "N ^ [x ^ 'N' ^ xi 0 t 'H N fi Me - ^^ N ^ fT" N' ^ N- / I H H

EJ  Ej
ESTRUCTURA  STRUCTURE

559  559
Me"N^ k-kN^ 0 1 J, H,N jj kl ^ n iY r°  Me "N ^ k-kN ^ 0 1 J, H, N jj kl ^ n iY r °

560#  560 #
Me"N-^ Y^i u m ° L N m >-Me ^ rll if T 1 ° H H  Me "N- ^ Y ^ i u m ° L N m> -Me ^ rll if T 1 ° H H

561#  561 #
k^^^k^N Et - H H  k ^^^ k ^ N Et - H H

562  562
Hf| ^ H Nk? k^^Nk,ry Et ^.0 MeON ^ N H H  Hf | ^ H Nk? k ^^ Nk, ry Et ^ .0 MeON ^ N H H

563#  563 #
HN || k^N^Jr^N^Et kk1" NNT" N H H  HN || k ^ N ^ Jr ^ N ^ Et kk1 "NNT" N H H

564  564
H|^ HNo° kk N^ f\k N kk H H  H | ^ HNo ° kk N ^ f \ k N kk H H

imagen136image136

EJEj

imagen137image137

571571

ESTRUCTURASTRUCTURE

572572

imagen138image138

573573

imagen139image139

574574

imagen140image140

imagen141image141

[Tabla 164][Table 164]

EJ  Ej
ESTRUCTURA  STRUCTURE

580  580
Me'N^ 0 JPr ri i t x0 H H HFM  Me'N ^ 0 JPr ri i t x0 H H HFM

581  581
q ^''SYr'o V^hAiT'na^ H H HFM  q ^ '' SYr'o V ^ hAiT'na ^ H H HFM

582  582
MexM^ JYY N Et fil l T ? HFM  MexM ^ JYY N Et fil l T? Hfm

Ej  Ex
Sin Datos  No data

1  one
Ej4 ESI+ 451  Ex4 ESI + 451

2  2
Ej4 ESI+ 463  Ex4 ESI + 463

3  3
Ej4 ESI+ 477  Ex4 ESI + 477

4  4
Ej4 ESI+ 491  Ex4 ESI + 491

5  5
Ej4 ESI+ 493  Ex4 ESI + 493

6  6
Ej4 ESI+ 509  Ex4 ESI + 509

7  7
Ej4 ESI+ 423  Ex4 ESI + 423

8  8
Ej4 ESI+ 449  Ex4 ESI + 449

9  9
Ej4 ESI+ 477  Ex4 ESI + 477

10  10
Ej4 FAB+ : 450  Ex4 FAB +: 450

11  eleven
Ej4 FAB+ : 450  Ex4 FAB +: 450

12  12
Ej4 FAB+ : 449  Ex4 FAB +: 449

13  13
Ej4 ESI+ 449  Ex4 ESI + 449

14  14
Ej4 ESI+ 449  Ex4 ESI + 449

15  fifteen
Ej4 ESI+ 449  Ex4 ESI + 449

16  16
Ej4 ESI+ 436  Ex4 ESI + 436

17  17
Ej4 ESI+ 436  Ex4 ESI + 436

18  18
Ej4 ESI+ 436  Ex4 ESI + 436

19  19
Ej19 ESI+ 449  Ex19 ESI + 449

20  twenty
Ej4 ESI+ 435  Ex4 ESI + 435

21  twenty-one
Ej4 ESI+ 435  Ex4 ESI + 435

22  22
Ej4 ESI+ 463  Ex4 ESI + 463

23  2. 3
Ej37 ESI+ 639  Ex37 ESI + 639

24  24
Ej4 ESI+ 435  Ex4 ESI + 435

25  25
Ej4 ESI+ 435  Ex4 ESI + 435

26  26
Ej4 ESI+ 421  Ex4 ESI + 421

27  27
Ej4 ESI+ 421  Ex4 ESI + 421

28  28
Ej37 ESI+ 535  Ex37 ESI + 535

29  29
Ej29 ESI+ 435  Ex29 ESI + 435

30  30
Ei405 FAB+: 477  Ei405 FAB +: 477

31  31
Ej31 FAB+: 513  Ex31 FAB +: 513

32  32
Ej4 ESI+ 477  Ex4 ESI + 477

33  33
Ej4 ESI+ 477  Ex4 ESI + 477

34  3. 4
Ej4 ESI+ 372  Ex4 ESI + 372

35  35
Ej4 FAB+: 436  Ex4 FAB +: 436

36  36
Ej4 ESI+ 400  Ex4 ESI + 400

37  37
Ej37 ESI+ 414  Ex37 ESI + 414

38  38
Ej4 ESI+ 428  Ex4 ESI + 428

39  39
Ej4 ESI+ 449  Ex4 ESI + 449

40  40
Ej4 ESI+ 463  Ex4 ESI + 463

41  41
Ej4 ESI+ 437  Ex4 ESI + 437

42  42
Ej4 ESI+ 436  Ex4 ESI + 436

43  43
Ej4 ESI-: 400  Ex4 ESI-: 400

44  44
Ej4 ESI+ 463  Ex4 ESI + 463

45  Four. Five
Ej4 ESI+ 449  Ex4 ESI + 449

46  46
Ej4 ESI+ 464  Ex4 ESI + 464

47  47
Ej4 ESI+ 392  Ex4 ESI + 392

48  48
Ej4 ESI+ 450  Ex4 ESI + 450

49  49
Ej4 ESI+ 426  Ex4 ESI + 426

50  fifty
Ej4 ESI+ 468  Ex4 ESI + 468

51  51
Ej4 ESI+ 454  Ex4 ESI + 454

52  52
Ej4 ESI+ 489  Ex4 ESI + 489

53  53
Ej4 FAB+: 388  Ex4 FAB +: 388

54  54
Ej4 FAB+: 450  Ex4 FAB +: 450

55  55
Ej4 ESI+ 449  Ex4 ESI + 449

56  56
Ej4 ESI+ 470  Ex4 ESI + 470

57  57
Ej4 ESI+ 456  Ex4 ESI + 456

58  58
Ej4 ESI+ 468  Ex4 ESI + 468

59  59
Ej4 ESI+ 442  Ex4 ESI + 442

60  60
Ej4 ESI+ 414  Ex4 ESI + 414

61  61
EJ4____ ESI+ 484  EJ4____ ESI + 484

Ej  Ex
Sin Datos  No data

62  62
Ej4 ESI+: 470  Ex4 ESI +: 470

63  63
Ej4 ESI+: 492  Ex4 ESI +: 492

64  64
Ej4 ESI+: 504  Ex4 ESI +: 504

65  65
Ej4 ESI+: 448  Ex4 ESI +: 448

66  66
EJ4____ ESI+: 490  EJ4____ ESI +: 490

[Tabla 1661[Table 1661

Ej  Ex
Sin Datos  No data

67  67
Ej4 ESI+: 408  Ex4 ESI +: 408

68  68
Ej4 ESI+: 434  Ex4 ESI +: 434

69  69
Ej4 FAB+: 382  Ex4 FAB +: 382

70  70
Ej4 FAB+: 409  Ex4 FAB +: 409

71  71
Ej4 ESI+: 381  Ex4 ESI +: 381

72  72
Ej4 FAB+: 410  Ex4 FAB +: 410

73  73
Ej4 ESI+: 478  Ex4 ESI +: 478

74  74
Ej4 ESI+: 506  Ex4 ESI +: 506

75  75
Ej4 ESI+: 518  Ex4 ESI +: 518

76  76
Ej4 ESI+: 492  Ex4 ESI +: 492

77  77
Ej4 ESI+: 464  Ex4 ESI +: 464

78  78
Ej4 ESI+: 502  Ex4 ESI +: 502

79  79
Ej4 ESI+: 476  Ex4 ESI +: 476

80  80
Ej4 ESI+: 482  Ex4 ESI +: 482

81  81
Ej4 ESI+: 456  Ex4 ESI +: 456

82  82
Ej4 ESI+: 428  Ex4 ESI +: 428

83  83
Ej4 ESI+: 469, 471  Ex4 ESI +: 469, 471

84  84
Ej84 ESI+: 447  Ex84 ESI +: 447

85  85
Ej84 ESI+: 433  Ex84 ESI +: 433

86  86
Ej84 ESI+: 434  Ex84 ESI +: 434

87  87
Ej4 ESI+: 434  Ex4 ESI +: 434

88  88
Ej4 ESI+: 392  Ex4 ESI +: 392

89  89
Ej84 ESI+: 400  Ex84 ESI +: 400

90  90
Ej4 ESI+: 372  Ex4 ESI +: 372

91  91
Ej4 ESI+: 520  Ex4 ESI +: 520

92  92
Ej4 ESI+: 508  Ex4 ESI +: 508

93  93
Ej4 ESI+: 488  Ex4 ESI +: 488

94  94
Ej4 ESI+: 434  Ex4 ESI +: 434

95  95
Ej4 ESI+: 462  Ex4 ESI +: 462

96  96
Ej4 ESI+: 446  Ex4 ESI +: 446

97  97
Ej4 ESI+: 472  Ex4 ESI +: 472

98  98
Ej4 ESI+: 474  Ex4 ESI +: 474

99  99
Ej4 ESI+: 460  Ex4 ESI +: 460

100  100
Ej4 ESI+: 392  Ex4 ESI +: 392

101  101
Ej84 FAB+: 419  Ex84 FAB +: 419

102  102
Ej84 FAB+: 475  Ex84 FAB +: 475

103  103
Ej84 FAB+: 448  Ex84 FAB +: 448

104  104
Ej4 ESI+: 426  Ex4 ESI +: 426

105  105
Ej4 ESI+: 426  Ex4 ESI +: 426

106  106
Ej4 ESI+: 434  Ex4 ESI +: 434

107  107
Ej4 ESI+: 422  Ex4 ESI +: 422

108  108
Ej84 ESI+: 433  Ex84 ESI +: 433

109  109
Ej84 ESI+: 448  Ex84 ESI +: 448

110  110
Ej84 ESI+: 448  Ex84 ESI +: 448

111  111
Ej84 FAB+: 406  Ex84 FAB +: 406

112  112
Ej146 ESI+: 420  Ex146 ESI +: 420

113  113
Ej4 ESI+: 436  Ex4 ESI +: 436

114  114
Ej4 ESI+: 358  Ex4 ESI +: 358

115  115
Ej4 ESI+: 392  Ex4 ESI +: 392

116  116
Ej4 ESI+: 392  Ex4 ESI +: 392

117  117
Ej84 ESI+: 423  Ex84 ESI +: 423

118  118
Ej4 ESI+: 494  Ex4 ESI +: 494

119  119
EJ4___ ESI+: 508  EJ4___ ESI +: 508

Ej  Ex
Sin Datos  No data

120  120
Ej4 ESI+ 482  Ex4 ESI + 482

121  121
Ej4 ESI+ 428  Ex4 ESI + 428

122  122
Ej4 ESI+ 484  Ex4 ESI + 484

123  123
Ej4 ESI+ 468  Ex4 ESI + 468

124  124
Ej4 ESI+ 414  Ex4 ESI + 414

125  125
Ej4 ESI+ 468  Ex4 ESI + 468

126  126
Ej4 ESI+ 18  Ex4 ESI + 18

127  127
Ej4 ESI+ 486  Ex4 ESI + 486

128  128
Ej4 ESI+ CM 00  Ex4 ESI + CM 00

129  129
Ej4 ESI+ 522  Ex4 ESI + 522

130  130
Ej4 ESI+ 480  Ex4 ESI + 480

131  131
Ej4 FAB+: 508  Ex4 FAB +: 508

132  132
Ej4 ESI+: 468  Ex4 ESI +: 468

[Tabla 1671[Table 1671

Ej  Ex
Sin Datos  No data

133  133
Ej4 FAB+: 414  Ex4 FAB +: 414

134  134
Ej4 ESI+: 522  Ex4 ESI +: 522

135  135
Ej4 FAB+: 534  Ex4 FAB +: 534

136  136
Ej4 FAB+: 444  Ex4 FAB +: 444

137  137
Ej4 ESI+: 498  Ex4 ESI +: 498

138  138
Ej4 ESI+: 482  Ex4 ESI +: 482

139  139
Ej4 FAB+: 428  Ex4 FAB +: 428

140  140
Ej4 ESI+ 536  Ex4 ESI + 536

141  141
Ej4 ESI+ 460  Ex4 ESI + 460

142  142
Ej4 ESI+ 432  Ex4 ESI + 432

143  143
Ej4 ESI+ 488  Ex4 ESI + 488

144  144
Ej4 ESI+ 474  Ex4 ESI + 474

145  145
Ej4 ESI+ 460  Ex4 ESI + 460

146  146
Ej146 ESI+ 468  Ex146 ESI + 468

147  147
Ej84 ESI+ 486  Ex84 ESI + 486

148  148
Ej84 ESI+ 448  Ex84 ESI + 448

149  149
Ej84 ESI+ 434  Ex84 ESI + 434

150  150
Ej84 ESI+ 427  Ex84 ESI + 427

151  151
Ej84 ESI+ 535  Ex84 ESI + 535

152  152
Ej84 ESI+ 427  Ex84 ESI + 427

153  153
Ej84 ESI+ 427  Ex84 ESI + 427

154  154
Ej4 ESI+ 448  Ex4 ESI + 448

155  155
Ej84 ESI+ 447  Ex84 ESI + 447

156  156
Ej84 ESI+ 443  Ex84 ESI + 443

157  157
Ej84 ESI+ 433  Ex84 ESI + 433

158  158
Ej84 ESI+ 433  Ex84 ESI + 433

159  159
Ej159 ESI+ 440  Ex159 ESI + 440

160  160
Ej84 ESI+ 427  Ex84 ESI + 427

161  161
Ej84 ESI+ 481  Ex84 ESI + 481

162  162
Ej84 ESI+ 427  Ex84 ESI + 427

163  163
Ej84 ESI+ 447  Ex84 ESI + 447

164  164
Ej84 ESI+ 406  Ex84 ESI + 406

165  165
Ej146 ESI+ 448  Ex146 ESI + 448

166  166
Ej84 ESI+ 434  Ex84 ESI + 434

167  167
Ej84 ESI+ 461  Ex84 ESI + 461

168  168
Ej84 ESI+ 497  Ex84 ESI + 497

169  169
Ej84 ESI+ 461  Ex84 ESI + 461

170  170
Ej84 ESI+ 448  Ex84 ESI + 448

171  171
Ej84 FAB+: 431  Ex84 FAB +: 431

172  172
Ej84 FAB+: 447  Ex84 FAB +: 447

173  173
Ej4 FAB-: 405  Ex4 FAB-: 405

174  174
Ej84 FAB-: 404  Ex84 FAB-: 404

175  175
Ej84 FAB+: 479  Ex84 FAB +: 479

176  176
Ej84 FAB+: 413  Ex84 FAB +: 413

177  177
Ej84 ESI+: 454  Ex84 ESI +: 454

Ej  Ex
Sin Datos  No data

178  178
Ej146 ESI+: 407  Ex146 ESI +: 407

179  179
Ej84 ESI+: 454  Ex84 ESI +: 454

180  180
Ej159 ESI+: 488  Ex159 ESI +: 488

181  181
Ej181 ESI+: 484, 486  Ex181 ESI +: 484, 486

182  182
Ej84 ESI+: 357  Ex84 ESI +: 357

183  183
Ej84 ESI+: 441  Ex84 ESI +: 441

184  184
Ej84 ESI+: 469  Ex84 ESI +: 469

185  185
Ej84 ESI+: 469  Ex84 ESI +: 469

186  186
Ej84 ESI+: 441  Ex84 ESI +: 441

187  187
Ej84 ESI+: 427  Ex84 ESI +: 427

188  188
Ej84 ESI+: 346  Ex84 ESI +: 346

189  189
Ej84 ESI+: 431  Ex84 ESI +: 431

190  190
Ej190 ESI+: 532  Ex190 ESI +: 532

191  191
Ej84 ESI+: 371  Ex84 ESI +: 371

192  192
Ej146 APCI/ESI+: 371  Ex146 APCI / ESI +: 371

193  193
Ej84 ESI+: 434  Ex84 ESI +: 434

194  194
Ej84 ESI+: 434  Ex84 ESI +: 434

195  195
Ej196 ESI+: 419  Ex196 ESI +: 419

196  196
Ej196 ESI+: 433  Ex196 ESI +: 433

197  197
Ej196 ESI+: 447  Ex196 ESI +: 447

198  198
Ej196 ESI+: 447  Ex196 ESI +: 447

[Tabla 1681[Table 1681

Ej  Ex
Sin Datos  No data

199  199
Ej196 ESI+: 461  Ex196 ESI +: 461

200  200
Ej196 ESI+: 515  Ex196 ESI +: 515

201  201
Ej196 ESI+: 523  Ex196 ESI +: 523

202  202
Ej196 ESI+: 447  Ex196 ESI +: 447

203  203
Ej196 ESI+: 475  Ex196 ESI +: 475

204  204
Ej196 ESI+: 491  Ex196 ESI +: 491

205  205
Ej196 ESI+: 433  Ex196 ESI +: 433

206  206
Ej196 ESI+: 433  Ex196 ESI +: 433

207  207
Ej196 ESI+: 418  Ex196 ESI +: 418

208  208
Ej196 ESI+: 448  Ex196 ESI +: 448

209  209
Ej196 ESI+: 448  Ex196 ESI +: 448

210  210
Ej196 ESI+: 496  Ex196 ESI +: 496

211  211
Ej196 ESI+: 405  Ex196 ESI +: 405

212  212
Ej196 ESI+: 405  Ex196 ESI +: 405

213  213
Ej196 ESI+: 419  Ex196 ESI +: 419

214  214
Ej196 ESI+: 495  Ex196 ESI +: 495

215  215
Ej196 ESI+: 495  Ex196 ESI +: 495

216  216
Ej196 ESI+: 419  Ex196 ESI +: 419

217  217
Ej196 ESI+: 447  Ex196 ESI +: 447

218  218
Ej196 ESI+: 420  Ex196 ESI +: 420

219  219
Ej196 ESI+: 434  Ex196 ESI +: 434

220  220
Ej196 ESI+: 438  Ex196 ESI +: 438

221  221
Ej196 ESI+: 391  Ex196 ESI +: 391

222  222
Ej196 ESI+: 405  Ex196 ESI +: 405

223  223
Ej196 ESI+: 473  Ex196 ESI +: 473

224  224
Ej196 ESI+: 447  Ex196 ESI +: 447

225  225
Ej196 ESI+: 447  Ex196 ESI +: 447

226  226
Ej196 ESI+: 449  Ex196 ESI +: 449

227  227
Ej196 ESI+: 463  Ex196 ESI +: 463

228  228
Ej196 ESI+: 515  Ex196 ESI +: 515

229  229
Ej196 ESI+: 523  Ex196 ESI +: 523

230  230
Ej196 ESI+: 433  Ex196 ESI +: 433

231  231
Ej196 ESI+: 433  Ex196 ESI +: 433

232  232
Ej196 ESI+: 433  Ex196 ESI +: 433

233  233
Ej196 ESI+: 433  Ex196 ESI +: 433

234  2. 3. 4
Ej196 ESI+: 433  Ex196 ESI +: 433

235  235
Ej196 ESI+: 434  Ex196 ESI +: 434

Ej  Ex
Sin Datos  No data

236  236
Ej196 ESI+: 434  Ex196 ESI +: 434

237  237
Ej196 ESI+: 436  Ex196 ESI +: 436

238  238
Ej196 ESI+: 448  Ex196 ESI +: 448

239  239
Ej196 ESI+: 448  Ex196 ESI +: 448

240  240
Ej196 ESI+: 447  Ex196 ESI +: 447

241  241
Ej196 ESI+: 447  Ex196 ESI +: 447

242  242
Ej196 ESI+: 420  Ex196 ESI +: 420

243  243
Ej196 ESI+: 420  Ex196 ESI +: 420

244  244
Ej196 ESI+: 405  Ex196 ESI +: 405

245  245
Ej196 ESI+: 406  Ex196 ESI +: 406

246  246
Ej196 ESI+: 462  Ex196 ESI +: 462

247  247
Ej196 ESI+: 476  Ex196 ESI +: 476

248  248
Ej196 ESI+: 447  Ex196 ESI +: 447

249  249
Ej196 ESI+: 462  Ex196 ESI +: 462

250  250
Ej196 ESI+: 463  Ex196 ESI +: 463

251  251
Ej196 ESI+: 448  Ex196 ESI +: 448

252  252
Ej196 ESI+: 433  Ex196 ESI +: 433

253  253
Ej196 ESI+: 447  Ex196 ESI +: 447

254  254
Ej196 ESI+: 434  Ex196 ESI +: 434

255  255
Ej196 ESI+: 379  Ex196 ESI +: 379

256  256
Ej196 ESI+: 393  Ex196 ESI +: 393

257  257
Ej196 ESI+: 407  Ex196 ESI +: 407

258  258
Ej196 ESI+: 421  Ex196 ESI +: 421

259  259
Ej196 ESI+: 421  Ex196 ESI +: 421

260  260
Ej196 ESI+: 421  Ex196 ESI +: 421

261  261
Ej196 ESI+: 407  Ex196 ESI +: 407

262  262
Ej196 ESI+: 380  Ex196 ESI +: 380

263  263
Ej196 ESI+: 394  Ex196 ESI +: 394

264  264
Ej196 ESI+: 408  Ex196 ESI +: 408

[Tabla 1691[Table 1691

Ej  Ex
Sin Datos  No data

265  265
Ej196 ESI+ 394  Ex196 ESI + 394

266  266
Ej196 ESI+ 410  Ex196 ESI + 410

267  267
Ej196 ESI+ 394  Ex196 ESI + 394

268  268
Ej196 ESI+ 438  Ex196 ESI + 438

269  269
Ej196 ESI+ 419  Ex196 ESI + 419

270  270
Ej196 ESI+ 481  Ex196 ESI + 481

271  271
Ej196 ESI+ 406  Ex196 ESI + 406

272  272
Ej196 ESI+ 434  Ex196 ESI + 434

273  273
Ej196 ESI+ 421  Ex196 ESI + 421

274  274
Ej196 ESI+ 394  Ex196 ESI + 394

275  275
Ej196 ESI+ 442  Ex196 ESI + 442

276  276
Ej196 ESI+ 413  Ex196 ESI + 413

277  277
Ej196 ESI+ 426  Ex196 ESI + 426

278  278
Ej196 ESI+ 456  Ex196 ESI + 456

279  279
Ej196 ESI+ 427  Ex196 ESI + 427

280  280
Ej196 ESI+ 528  Ex196 ESI + 528

281  281
Ej84 ESI+ 427  Ex84 ESI + 427

282  282
Ej84 ESI+ 455  Ex84 ESI + 455

283  283
Ej84 ESI+ 370  Ex84 ESI + 370

284  284
Ej84 ESI+ 567  Ex84 ESI + 567

285  285
Ej84 ESI+ 463  Ex84 ESI + 463

286  286
Ej84 ESI+ 483  Ex84 ESI + 483

287  287
Ej84 ESI+ 447  Ex84 ESI + 447

288  288
Ej84 ESI+ 443  Ex84 ESI + 443

289  289
Ej84 ESI+ 463  Ex84 ESI + 463

290  290
Ej84 ESI+ 535  Ex84 ESI + 535

291  291
Ej84 ESI+ 427  Ex84 ESI + 427

292  292
Ej84 ESI+ 396  Ex84 ESI + 396

293  293
Ej84 ESI+ 414  Ex84 ESI + 414

Ej  Ex
Sin Datos  No data

294  294
Ej84 ESI+ 525  Ex84 ESI + 525

295  295
Ej84 ESI+ 549  Ex84 ESI + 549

296  296
Ej146 ESI+ 448  Ex146 ESI + 448

297  297
Ej84 ESI+ 433  Ex84 ESI + 433

298  298
Ej84 ESI+ 407  Ex84 ESI + 407

299  299
Ej84 ESI+ 378  Ex84 ESI + 378

300  300
Ej84 ESI+ 404  Ex84 ESI + 404

301  301
Ej84 ESI+ 461  Ex84 ESI + 461

302  302
Ei302 ESI+ 489  Ei302 ESI + 489

303  303
Ej84 ESI+ 424  Ex84 ESI + 424

304  304
Ej84 ESI+ 396  Ex84 ESI + 396

305  305
Ej84 ESI+ 412  Ex84 ESI + 412

306  306
Ej84 ESI+ 407  Ex84 ESI + 407

307  307
Ej84 ESI+ 547  Ex84 ESI + 547

308  308
Ej84 ESI+ 429  Ex84 ESI + 429

309  309
Ej309 ESI+ 399  Ex309 ESI + 399

310  310
Ej310 ESI+ 453  Ex310 ESI + 453

311  311
Ej84 ESI+ 549  Ex84 ESI + 549

312  312
Ej84 ESI+ 428  Ex84 ESI + 428

313  313
Ej84 ESI+ 496  Ex84 ESI + 496

314  314
Ej84 ESI+ 494  Ex84 ESI + 494

315  315
Ej84 ESI+ 427  Ex84 ESI + 427

316  316
Ej84 ESI+ 480  Ex84 ESI + 480

317  317
Ej84 ESI+ 466  Ex84 ESI + 466

318  318
Ej84 ESI+ 494  Ex84 ESI + 494

319  319
Ej84 ESI+ 401  Ex84 ESI + 401

320  320
Ej84 ESI+ 447  Ex84 ESI + 447

321  321
Ej84 ESI+ 440  Ex84 ESI + 440

322  322
Ej302 ESI+ 468  Ex302 ESI + 468

323  323
Ej146 ESI+ 502  Ex146 ESI + 502

324  324
Ej84 ESI+ 440  Ex84 ESI + 440

325  325
Ej84 ESI+ 454  Ex84 ESI + 454

326  326
Ej84 ESI+ 526  Ex84 ESI + 526

327  327
Ej84 ESI+ 414  Ex84 ESI + 414

328  328
Ej84 ESI+ 410  Ex84 ESI + 410

329  329
Ej84 ESI+ 441  Ex84 ESI + 441

330  330
Ej84 ESI+ 414  Ex84 ESI + 414

[Tabla 1701[Table 1701

Ej  Ex
Sin Datos  No data

331  331
Ej84 ESI+ 409  Ex84 ESI + 409

332  332
Ej84 ESI+ 508  Ex84 ESI + 508

333  333
Ej84 ESI+ 385  Ex84 ESI + 385

334  334
Ej84 Yes!+: 482  Ex84 Yes! +: 482

335  335
Ej84 ESI+ 480  Ex84 ESI + 480

336  336
Ej84 ESI+ 468  Ex84 ESI + 468

337  337
Ej84 ESI+ 453  Ex84 ESI + 453

338  338
Ej84 ESI+ 512  Ex84 ESI + 512

339  339
Ej84 ESI+ 484  Ex84 ESI + 484

340  340
Ej84 ESI+ 567  Ex84 ESI + 567

341  341
Ej84 ESI+ 537  Ex84 ESI + 537

342  342
Ej84 ESI+ 466  Ex84 ESI + 466

343  343
Ej343 ESI+ 468  Ex343 ESI + 468

344  344
Ej84 ESI+ 512  Ex84 ESI + 512

345  3. 4. 5
Ej159 ESI+ 546  Ex159 ESI + 546

346  346
Ej381 ESI+ 446  Ex381 ESI + 446

347  347
Ej84 ESI+ 454  Ex84 ESI + 454

348  348
Ej84 ESI+ 581  Ex84 ESI + 581

349  349
Ej84 ESI+ 581  Ex84 ESI + 581

350  350
Ej84 ESI+ 570  Ex84 ESI + 570

351  351
Ej146 ESI+ 549  Ex146 ESI + 549

Ej  Ex
Sin Datos  No data

352  352
Ej84 ESI+ 449  Ex84 ESI + 449

353  353
Ej84 ESI+ 463  Ex84 ESI + 463

354  354
Ej84 ESI+ 522  Ex84 ESI + 522

355  355
Ej84 ESI+ 484  Ex84 ESI + 484

356  356
Ej84 ESI+ 539  Ex84 ESI + 539

357  357
Ej84 ESI+ 441  Ex84 ESI + 441

358  358
Ej381 ESI+ 439  Ex381 ESI + 439

359  359
Ej84 ESI+ 439  Ex84 ESI + 439

360  360
Ej84 ESI+ 636  Ex84 ESI + 636

361  361
Ej84 ESI+ 469  Ex84 ESI + 469

362  362
Ej84 ESI+ 468  Ex84 ESI + 468

363  363
Ej84 ESI+ 538  Ex84 ESI + 538

364  364
Ej84 ESI+ 560  Ex84 ESI + 560

365  365
Ej84 ESI+ 455  Ex84 ESI + 455

366  366
Ej84 ESI+ 476  Ex84 ESI + 476

367  367
Ej84 ESI+ 455  Ex84 ESI + 455

368  368
Ej84 ESI+ 442  Ex84 ESI + 442

369  369
Ej84 ESI+ 477  Ex84 ESI + 477

370  370
Ej146 ESI+ 605  Ex146 ESI + 605

371  371
Ej84 ESI+ 538  Ex84 ESI + 538

372  372
Ej84 ESI+ 560  Ex84 ESI + 560

373  373
Ej84 ESI+ 631  Ex84 ESI + 631

374  374
Ej84 ESI+ 456  Ex84 ESI + 456

375  375
Ej84 ESI+ 455  Ex84 ESI + 455

376  376
Ej84 ESI+ 552  Ex84 ESI + 552

377  377
Ej84 ESI+ 468  Ex84 ESI + 468

378  378
Ej84 ESI+ 551  Ex84 ESI + 551

379  379
Ej84 ESI+ 464  Ex84 ESI + 464

380  380
Ej84 ESI+ 442  Ex84 ESI + 442

381  381
Ej381 ESI+ 469  Ex381 ESI + 469

382  382
Ej84 ESI+ 569  Ex84 ESI + 569

383  383
Ej84 ESI+ 484  Ex84 ESI + 484

384  384
Ej84 ESI+ 522  Ex84 ESI + 522

385  385
Ej84 ESI+ 617  Ex84 ESI + 617

386  386
Ej84 ESI+ 644  Ex84 ESI + 644

387  387
Ej84 ESI+ 453  Ex84 ESI + 453

388  388
Ei343 ESI+ 619  Ei343 ESI + 619

389  389
Ei343 ESI+ 646  Ei343 ESI + 646

390  390
Ej84 ESI-: 488  Ex84 ESI-: 488

391  391
Ej84 ESI+ 482  Ex84 ESI + 482

392  392
Ej84 ESI+ 565  Ex84 ESI + 565

393  393
Ej84 ESI+ 540  Ex84 ESI + 540

394  394
Ej381 ESI+ 440  Ex381 ESI + 440

395  395
Ej302 ESI+ 522  Ex302 ESI + 522

396  396
Ej302 ESI+ 524  Ex302 ESI + 524

[Tabla 1711[Table 1711

Ej  Ex
Sin Datos  No data

397  397
Ej84 ESI+: 543  Ex84 ESI +: 543

398  398
Ej84 ESI-: 479  Ex84 ESI-: 479

399  399
Ej84 ESI+: 562  Ex84 ESI +: 562

400  400
Ej84 ESI+: 434, 436  Ex84 ESI +: 434, 436

401  401
Ej84 ESI+: 484  Ex84 ESI +: 484

402  402
Ej84 ESI+: 536  Ex84 ESI +: 536

403  403
Ej84 ESI+: 537  Ex84 ESI +: 537

404  404
Ej84 ESI+: 522  Ex84 ESI +: 522

405  405
Ej405 ESI+: 481  Ex405 ESI +: 481

406  406
Ej84 ESI+: 536  Ex84 ESI +: 536

407  407
Ej84 ESI+: 536  Ex84 ESI +: 536

408  408
Ej84 ESI+: 536  Ex84 ESI +: 536

409  409
Ej84 ESI+: 550  Ex84 ESI +: 550

Ej  Ex
Sin Datos  No data

410  410
Ej84 ESI+: 484  Ex84 ESI +: 484

411  411
Ej84 ESI+: 441  Ex84 ESI +: 441

412  412
Ej84 ESI+: 456  Ex84 ESI +: 456

413  413
Ej84 ESI+: 468  Ex84 ESI +: 468

414  414
Ej84 ESI+: 482  Ex84 ESI +: 482

415  415
Ej31 ESI+: 518  Ex31 ESI +: 518

416  416
Ei302 ESI+: 482  Ei302 ESI +: 482

417  417
Ej302 ESI+: 540  Ex302 ESI +: 540

418  418
Ej84 ESI+: 607  Ex84 ESI +: 607

419  419
Ej381 ESI+: 508  Ex381 ESI +: 508

420  420
Ej84 ESI+: 554  Ex84 ESI +: 554

421  421
Ej381 ESI+: 454  Ex381 ESI +: 454

422  422
Ej146 ESI+: 535  Ex146 ESI +: 535

423  423
Ej302 ESI+: 590  Ex302 ESI +: 590

424  424
Ej302 ESI+: 536  Ex302 ESI +: 536

425  425
Ej302 ESI+: 550  Ex302 ESI +: 550

426  426
Ej302 ESI+: 496  Ex302 ESI +: 496

427  427
Ej84 ESI+: 496  Ex84 ESI +: 496

428  428
Ej84 ESI+: 555  Ex84 ESI +: 555

429  429
Ej84 ESI+: 576  Ex84 ESI +: 576

430  430
Ej84 ESI+: 518  Ex84 ESI +: 518

431  431
Ej302 ESI+: 521  Ex302 ESI +: 521

432  432
Ej84 ESI+: 553  Ex84 ESI +: 553

433  433
Ej381 ESI+: 453  Ex381 ESI +: 453

434  434
Ej31 ESI+: 531  Ex31 ESI +: 531

435  435
Ej84 ESI+: 564  Ex84 ESI +: 564

436  436
Ej436 ESI+: 550  Ex436 ESI +: 550

437  437
Ej436 ESI+: 550  Ex436 ESI +: 550

438  438
Ej438 ESI+: 655  Ex.438 ESI +: 655

439  439
Ej438 ESI+: 655  Ex.438 ESI +: 655

440  440
Ej84 ESI+: 453  Ex84 ESI +: 453

441  441
Ej84 ESI+: 483  Ex84 ESI +: 483

442  442
Ej84 ESI+: 4488  Ex84 ESI +: 4488

443  443
Ej84 ESI+: 483  Ex84 ESI +: 483

444  444
Ej84 ESI+: 566  Ex84 ESI +: 566

445  445
Ej84 ESI+: 544  Ex84 ESI +: 544

446  446
Ej84 ESI+: 597  Ex84 ESI +: 597

447  447
Ej302 ESI+: 602  Ex302 ESI +: 602

448  448
Ej84 ESI+: 550  Ex84 ESI +: 550

449  449
Ej302 ESI+: 642  Ex302 ESI +: 642

450  450
Ej302 ESI-: 636  Ex302 ESI-: 636

451  451
Ej302 ESI+: 467  Ex302 ESI +: 467

452  452
Ej84 ESI+: 482  Ex84 ESI +: 482

453  453
Ej84 ESI+: 609  Ex84 ESI +: 609

454  454
Ej84 ESI+: 482  Ex84 ESI +: 482

455  455
Ej84 ESI+: 607  Ex84 ESI +: 607

456  456
Ej84 ESI+: 536  Ex84 ESI +: 536

457  457
Ej84 ESI+: 566  Ex84 ESI +: 566

458  458
Ej84 APCI/ESI+: 511  Ex84 APCI / ESI +: 511

459  459
Ej84 ESI+: 581  Ex84 ESI +: 581

460  460
Ej534 ESI+: 507  Ex534 ESI +: 507

461  461
Ej84 ESI+: 522  Ex84 ESI +: 522

462  462
Ej405 ESI+: 549  Ex405 ESI +: 549

[Tabla 1721[Table 1721

Ej  Ex
Sin Datos  No data

463  463
Ej405 ESI+: 641  Ex405 ESI +: 641

464  464
Ej302 ESI+: 644  Ex302 ESI +: 644

465  465
Ej84 ESI+: 561  Ex84 ESI +: 561

466  466
Ej84 ESI+: 565  Ex84 ESI +: 565

467  467
Ej84 ESI+: 570  Ex84 ESI +: 570

Ej  Ex
Sin Datos  No data

468  468
Ej381 ESI+ 470  Ex381 ESI + 470

469  469
Ei302 ESI+ 495  Ei302 ESI + 495

1470  1470
Ei302 ESI+ 535  Ei302 ESI + 535

471  471
Ej302 ESI+ 449  Ex302 ESI + 449

472  472
Ej84 ESI+ 449  Ex84 ESI + 449

473  473
Ej84 ESI+ 607  Ex84 ESI + 607

474  474
Ej381 ESI+ 507  Ex381 ESI + 507

475  475
Ej84 ESI+ 482  Ex84 ESI + 482

476  476
Ej84 ESI+ 471  Ex84 ESI + 471

477  477
Ej84 ESI+ 469  Ex84 ESI + 469

478  478
Ej84 ESI+ 567  Ex84 ESI + 567

479  479
Ej84 ESI+ 554  Ex84 ESI + 554

480  480
Ej84 ESI+ 469  Ex84 ESI + 469

481  481
Ej84 ESI+ 499  Ex84 ESI + 499

482  482
Ej159 ESI+ 533  Ex159 ESI + 533

483  483
Ej84 ESI+ 565  Ex84 ESI + 565

484  484
Ej84 ESI+ 511  Ex84 ESI + 511

485  485
Ej84 ESI+ 547  Ex84 ESI + 547

486  486
Ej84 ESI+ 530  Ex84 ESI + 530

487  487
Ej84 ESI+ 525  Ex84 ESI + 525

488  488
Ej302 ESI+ 512  Ex302 ESI + 512

489  489
Ej302 ESI+ 552  Ex302 ESI + 552

490  490
Ej84 ESI+ 579  Ex84 ESI + 579

491  491
Ej84 ESI+ 579  Ex84 ESI + 579

492  492
Ej302 ESI+ 608  Ex302 ESI + 608

493  493
Ej84 ESI+ 593  Ex84 ESI + 593

494  494
Ej84 ESI+ 593  Ex84 ESI + 593

495  495
Ej495 ESI+ 489  Ex495 ESI + 489

496  496
Ej84 FAB+. 553  Ex84 FAB +. 553

497  497
Ej84 ESI+ 553  Ex84 ESI + 553

498  498
Ej84 ESI+ 540  Ex84 ESI + 540

499  499
Ej499 ESI+ 573  Ex.499 ESI + 573

500  500
Ej84 FAB+: 540  Ex84 FAB +: 540

501  501
Ej84 ESI+ 485  Ex84 ESI + 485

502  502
Ej84 ESI+ 499  Ex84 ESI + 499

503  503
Ej84 ESI+ 512  Ex84 ESI + 512

504  504
Ej84 ESI+ 498  Ex84 ESI + 498

505  505
Ej84 ESI+ 567  Ex84 ESI + 567

506  506
Ej84 ESI+ 551  Ex84 ESI + 551

507  507
Ej84 APCI/ESI+: 626  Ex84 APCI / ESI +: 626

508  508
Ej508 APCI/ESI+: 446  Ex508 APCI / ESI +: 446

509  509
Ej84 ESI+ 539  Ex84 ESI + 539

510  510
Ej84 ESI+ 567  Ex84 ESI + 567

511  511
Ej84 ESI+ 554  Ex84 ESI + 554

512  512
Ej84 ESI+ 537  Ex84 ESI + 537

513  513
Ej84 ESI+ 611  Ex84 ESI + 611

514  514
Ej302 ESI+ 521  Ex302 ESI + 521

515  515
Ej84 ESI+ 532  Ex84 ESI + 532

516  516
Ej84 ESI+ 568  Ex84 ESI + 568

517  517
Ej146 ESI+ 651  Ex146 ESI + 651

518  518
Ej381 ESI+ 551  Ex381 ESI + 551

519  519
Ej84 ESI+ 572  Ex84 ESI + 572

520  520
Ej84 ESI+ 663  Ex84 ESI + 663

521  521
Ej84 ESI+ 594  Ex84 ESI + 594

522  522
Ej84 ESI+ 608  Ex84 ESI + 608

523  523
Ej84 ESI+ 494  Ex84 ESI + 494

524  524
Ej84 ESI+ 514  Ex84 ESI + 514

525  525
Ej84 ESI+ 561  Ex84 ESI + 561

526  526
Ej84 ESI+ 511  Ex84 ESI + 511

527  527
Ej84 ESI+ 644  Ex84 ESI + 644

528  528
Ej84 ESI+ 547  Ex84 ESI + 547

Ej  Ex
Sin Datos  No data

529  529
Ej84 ESI+ 525  Ex84 ESI + 525

530  530
Ej84 ESI+ 483  Ex84 ESI + 483

531  531
Ej84 ESI+ 499  Ex84 ESI + 499

532  532
Ej159 ESI+ 517  Ex159 ESI + 517

533  533
Ej159 ESI+  Ex159 ESI +
533  533

534  534
Ei534 ESI+ 536  Ei534 ESI + 536

535  535
Ej84 ESI+ 564  Ex84 ESI + 564

536  536
Ej495 ESI+ 473  Ex495 ESI + 473

537  537
Ej495 ESI+ 489  Ex495 ESI + 489

538  538
Ej499 ESI+ 557  Ex.499 ESI + 557

539  539
Ej499 ESI+ 573  Ex.499 ESI + 573

540  540
Ej84 ESI+ 573  Ex84 ESI + 573

541  541
Ej84 ESI+ 559  Ex84 ESI + 559

542  542
Ej84 APCI/ESI+: 613  Ex84 APCI / ESI +: 613

543  543
Ej84 ESI+ 613  Ex84 ESI + 613

544  544
Ej84 ESI+ 550  Ex84 ESI + 550

545  545
Ej84 ESI+ 440  Ex84 ESI + 440

546  546
Ej84 ESI+ 523  Ex84 ESI + 523

547  547
Ej84 ESI+ 553  Ex84 ESI + 553

548  548
Ej84 ESI+ 470  Ex84 ESI + 470

549  549
Ej343 ESI+ 537  Ex343 ESI + 537

550  550
Ej84 ESI+ 458  Ex84 ESI + 458

551  551
Ej302 ESI+ 553  Ex302 ESI + 553

552  552
Ej302 ESI+ 523  Ex302 ESI + 523

553  553
Ej84 ESI+ 484  Ex84 ESI + 484

554  554
Ej84 ESI+ 454  Ex84 ESI + 454

555  555
Ej84 ESI+ 472  Ex84 ESI + 472

556  556
Ej84 ESI+ 567  Ex84 ESI + 567

557  557
Ej84 ESI+ 541  Ex84 ESI + 541

558  558
Ej84 ESI+ 537  Ex84 ESI + 537

559  559
Ej84 ESI+ 555  Ex84 ESI + 555

560  560
Ej84 APCI/ESI+: 535  Ex84 APCI / ESI +: 535

561  561
Ej84 ESI+ 556  Ex84 ESI + 556

562  562
Ej381 ESI+ 456  Ex381 ESI + 456

563  563
Ej84 ESI+ 524  Ex84 ESI + 524

564  564
Ej381 ESI+ 426  Ex381 ESI + 426

565  565
Ej84 ESI+ 454  Ex84 ESI + 454

566  566
Ej84 ESI+ 537  Ex84 ESI + 537

567  567
Ej343 ESI+ 468  Ex343 ESI + 468

568  568
Ej146 ESI+ 605  Ex146 ESI + 605

569  569
Ej84 ESI+ 551  Ex84 ESI + 551

570  570
Ej343 ESI+ 619  Ex343 ESI + 619

571  571
Ej84 ESI+ 565  Ex84 ESI + 565

572  572
Ej302 ESI+ 496  Ex302 ESI + 496

573  573
Ej84 ESI+ 565  Ex84 ESI + 565

574  574
Ej84 ESI+ 537  Ex84 ESI + 537

575  575
Ej499 ESI+ 557  Ex.499 ESI + 557

576  576
Ej84 ESI+ 523  Ex84 ESI + 523

577  577
Ej84 ESI+ 553  Ex84 ESI + 553

578  578
Ej343 ESI+ 537  Ex343 ESI + 537

579  579
Ej84 ESI+ 441  Ex84 ESI + 441

580  580
Ej84 ESI+ 484  Ex84 ESI + 484

581  581
Ej84 ESI+ 454  Ex84 ESI + 454

582  582
Ej84 ESI+ 537  Ex84 ESI + 537

Ej  Ex
Datos  Data

86  86
RMN 'H (DMSO-d6): 1,19 (3H, t, J = 7,8 Hz), 1,33-1,50 (4H, m), 1,79-1,95 (4H, m), 2,60 (2H, q, J = 7,8 Hz), 3,21 (3H, s), 3,37-3,49 (1H, m), 3,89-4,01 (1H, m), 4,54 (1H, d, J = 4,4 Hz), 6,76 (1H, d, J = 7,9 Hz), 7,33-7,42 (1H, m), 7,44-7,57 (2H, m), 7,58-7,65 (1H, m), 7,96-8,03 (1H, m), 8,15-8,21 (1H, m), 11,59 (1H, s).  1 H NMR (DMSO-d6): 1.19 (3H, t, J = 7.8 Hz), 1.33-1.50 (4H, m), 1.79-1.95 (4H, m) , 2.60 (2H, q, J = 7.8 Hz), 3.21 (3H, s), 3.37-3.49 (1H, m), 3.89-4.01 (1H, m ), 4.54 (1H, d, J = 4.4 Hz), 6.76 (1H, d, J = 7.9 Hz), 7.33-7.42 (1H, m), 7.44 -7.57 (2H, m), 7.58-7.65 (1H, m), 7.96-8.03 (1H, m), 8.15-8.21 (1H, m), 11 , 59 (1H, s).

110  110
RMN ‘H (DMSO-d6): 1,13-1,25 (6H, m), 1,46-1,64 (6H, m), 1,79-1,91 (2H, m), 2,61 (2H, q, J = 7,4 Hz), 3,21 (3H, s), 3,94-4,09 (1H, m), 4,26 (1H, s), 6,72 (1H, d, J = 7,9 Hz), 7,33-7,42 (1H, m), 7,44-7,58 (2H, m), 7,59-7,66 (1H, m), 7,98-8,04 (1H, m), 8,16-8,20 (1H, m), 11,58 (1H, s).  1 H NMR (DMSO-d6): 1.13-1.25 (6H, m), 1.46-1.64 (6H, m), 1.79-1.91 (2H, m), 2, 61 (2H, q, J = 7.4 Hz), 3.21 (3H, s), 3.94-4.09 (1H, m), 4.26 (1H, s), 6.72 (1H , d, J = 7.9 Hz), 7.33-7.42 (1H, m), 7.44-7.58 (2H, m), 7.59-7.66 (1H, m), 7.98-8.04 (1H, m), 8.16-8.20 (1H, m), 11.58 (1H, s).

284  284
RMN ’H (CDCl3): 1,26-1,36 (5H, m), 1,48-1,56 (2H, m), 1,68-1,76 (2H, m), 1,95 (2H, d, J = 11,6 Hz), 2,08 (2H, d, J = 10,4 Hz), 2,26 (2H, d, J = 11,6 Hz), 2,30 (3H, s), 2,30-2,73 (13H, m), 3,64-3,74 (4H, m), 3,93-3,97 (4H, m), 4,52 (1H, d, J = 7,2 Hz), 5,13 (1H, s.a.), 6,50 (1 H, dd, J = 2,4 Hz, 9,2 Hz), 6,58 (1 H, d, J = 2,4 Hz), 7,46 (1 H, s.a.), 8,39 (1H, d, J = 8,8 Hz), 10,98 (1H, s).  NMR 'H (CDCl3): 1.26-1.36 (5H, m), 1.48-1.56 (2H, m), 1.68-1.76 (2H, m), 1.95 ( 2H, d, J = 11.6 Hz), 2.08 (2H, d, J = 10.4 Hz), 2.26 (2H, d, J = 11.6 Hz), 2.30 (3H, s), 2.30-2.73 (13H, m), 3.64-3.74 (4H, m), 3.93-3.97 (4H, m), 4.52 (1H, d, J = 7.2 Hz), 5.13 (1H, sa), 6.50 (1 H, dd, J = 2.4 Hz, 9.2 Hz), 6.58 (1 H, d, J = 2.4 Hz), 7.46 (1 H, sa), 8.39 (1H, d, J = 8.8 Hz), 10.98 (1H, s).

325  325
RMN 'H (DMSo-d6): 1,17 (3H, t, J = 7,4 Hz), 1,22-1,48 (4H, m), 1,84-2,00 (4H, m), 2,25 (3H, s), 2,44-2,59 (6H, m), 3,00-3,12 (4H, m), 3,43 (1H, m), 3,80 (1H, m), 4,56 (1H, d, J = 4,7 Hz), 6,63 (1H, d, J = 8,0 Hz), 6,87 (2H, d, J = 9,2 Hz), 7,13 (1H, a), 7,47 (1H, a), 7,51 (2H, d, J = 9,2 Hz), 10,9 (1H, s).  NMR 'H (DMSo-d6): 1.17 (3H, t, J = 7.4 Hz), 1.22-1.48 (4H, m), 1.84-2.00 (4H, m) , 2.25 (3H, s), 2.44-2.59 (6H, m), 3.00-3.12 (4H, m), 3.43 (1H, m), 3.80 (1H , m), 4.56 (1H, d, J = 4.7 Hz), 6.63 (1H, d, J = 8.0 Hz), 6.87 (2H, d, J = 9.2 Hz ), 7.13 (1H, a), 7.47 (1H, a), 7.51 (2H, d, J = 9.2 Hz), 10.9 (1H, s).

328  328
RMN lH (CdCI3): 1,25-1,67 (7H, m), 2,04 (2H, m), 2,17-2,22 (2H, m), 2,48-2,55 (2H, m), 3,72 (1H, m), 4,03 (3H, s), 4,05 (1H, m), 4,60 (1H, m), 5,19 (1H, m), 7,44 (1H, m), 7,51 (1H, m), 7,62 (1H, m), 7,78 (1H, s), 7,88 (1H, s), 11,14 (1H, s.a.).  1 H NMR (CdCI3): 1.25-1.67 (7H, m), 2.04 (2H, m), 2.17-2.22 (2H, m), 2.48-2.55 (2H , m), 3.72 (1H, m), 4.03 (3H, s), 4.05 (1H, m), 4.60 (1H, m), 5.19 (1H, m), 7 , 44 (1H, m), 7.51 (1H, m), 7.62 (1H, m), 7.78 (1H, s), 7.88 (1H, s), 11.14 (1H, sa).

340  340
RMN 1H (CDCI3): 1,22-1,54 (7H, m), 1,74-1,94 (4H, m), 2,01-2,10 (2H, m), 2,16-2,26 (2H, m), 2,30 (3H, s), 2,322,74 (13H, m), 3,50 (2H, d, J = 11,4 Hz), 3,65-3,76 (1H, m), 3,87 (3H, s), 3,92-4,03 (1H, m), 4,52 (1H, d, J = 7,3 Hz), 5,12 (1H, s.a.), 6,71 (1H, s), 6,84-6,90 (2H, m), 7,45-7,55 (2H, m), 10,74 (1H, s).  1H NMR (CDCI3): 1.22-1.54 (7H, m), 1.74-1.94 (4H, m), 2.01-2.10 (2H, m), 2.16-2 , 26 (2H, m), 2.30 (3H, s), 2,322.74 (13H, m), 3.50 (2H, d, J = 11.4 Hz), 3.65-3.76 ( 1H, m), 3.87 (3H, s), 3.92-4.03 (1H, m), 4.52 (1H, d, J = 7.3 Hz), 5.12 (1H, sa ), 6.71 (1H, s), 6.84-6.90 (2H, m), 7.45-7.55 (2H, m), 10.74 (1H, s).

[Tabla 1751[Table 1751

Ej  Ex
Datos  Data

341  341
RMN lH (DMSO-d6): 1,17 (3H, t, J = 7,4 Hz), 1,21-1,60 (6H, m), 1,75-2,00 (6H, m), 2,14 (3H, s), 2,20-2,72 (13H, m), 3,43 (1H, m), 3,58 (2H, m), 3,80 (1H, m), 4,57 (1H, d, J = 4,4 Hz), 6,63 (1H, d, J = 7,3 Hz), 6,86 (2H, d, J = 8,7 Hz), 7,13 (1H, s.a.), 7,40-7,60 (3H, m), 10,92 (1H, s).  1 H NMR (DMSO-d6): 1.17 (3H, t, J = 7.4 Hz), 1.21-1.60 (6H, m), 1.75-2.00 (6H, m), 2.14 (3H, s), 2.20-2.72 (13H, m), 3.43 (1H, m), 3.58 (2H, m), 3.80 (1H, m), 4 , 57 (1H, d, J = 4.4 Hz), 6.63 (1H, d, J = 7.3 Hz), 6.86 (2H, d, J = 8.7 Hz), 7.13 (1H, sa), 7.40-7.60 (3H, m), 10.92 (1H, s).

343  343
RMN lH (DMSO-d6): 1,14 (6h, d, J =6,6 Hz), 1,21-1,48 (4H, m), 1,85-1,98 (4H, m), 2,22 (3H, s), 2,41-2,48 (4H, m), 2,99-3,18 (5H, m), 3,37-3,48 (1H, m), 3,74-3,87 (1H, m), 4,56 (1H, d, J = 4,7 Hz), 6,67 (1H, d, J = 7,6 Hz), 6,86 (2H, d, J = 9,0 Hz), 7,11-7,18 (1H, m), 7,40-7,47 (1H, m), 7,50 (2H, d, J = 9,0 Hz), 10,91 (1H, s)  1 H NMR (DMSO-d6): 1.14 (6h, d, J = 6.6 Hz), 1.21-1.48 (4H, m), 1.85-1.98 (4H, m), 2.22 (3H, s), 2.41-2.48 (4H, m), 2.99-3.18 (5H, m), 3.37-3.48 (1H, m), 3, 74-3.87 (1H, m), 4.56 (1H, d, J = 4.7 Hz), 6.67 (1H, d, J = 7.6 Hz), 6.86 (2H, d , J = 9.0 Hz), 7.11-7.18 (1H, m), 7.40-7.47 (1H, m), 7.50 (2H, d, J = 9.0 Hz) , 10.91 (1H, s)

347  347
RMN lH (DMSO-d6): 1,10-1,49 (7H, m), 1,80-1,96 (4H, m), 2,22 (3H, s), 2,40-2,61 (6H, m), 3,06-3,18 (4H, m), 3,43 (1H, m), 3,86 (1H, m), 4,56 (1H, d, J = 4,3 Hz), 6,57 (1H, m), 6,63 (1H, d, J = 7,6 Hz), 6,91 (1H, m), 7,10 (1H, m), 7,18 (1H, a), 7,29 (1H, m), 7,51 (1H, s.a.), 11,09 (1H, s).  1 H NMR (DMSO-d6): 1.10-1.49 (7H, m), 1.80-1.96 (4H, m), 2.22 (3H, s), 2.40-2.61 (6H, m), 3.06-3.18 (4H, m), 3.43 (1H, m), 3.86 (1H, m), 4.56 (1H, d, J = 4.3 Hz), 6.57 (1H, m), 6.63 (1H, d, J = 7.6 Hz), 6.91 (1H, m), 7.10 (1H, m), 7.18 ( 1H, a), 7.29 (1H, m), 7.51 (1H, sa), 11.09 (1H, s).

354  354
RMN 1H (DMSO-d6): 1,12-1,32 (5H, m), 1,36-1,50 (2H, m), 1,78-1,96 (4H, m), 2,22 (3H, s), 2,35-2,63 (6H, m), 2,78-2,88 (4H, m), 3,41 (1H, m), 3,87 (1H, m), 4,55 (1H, d, J = 3,9 Hz), 6,68 (1H, d, J = 7,9 Hz), 7,27 (1H, s.a.), 7,46 (1H, d, J = 8,7 Hz), 7,56 (1H, s.a.), 7,61 (1H, m), 8,18 (1H, m), 11,37 (1H, s)  1H NMR (DMSO-d6): 1.12-1.32 (5H, m), 1.36-1.50 (2H, m), 1.78-1.96 (4H, m), 2.22 (3H, s), 2.35-2.63 (6H, m), 2.78-2.88 (4H, m), 3.41 (1H, m), 3.87 (1H, m), 4.55 (1H, d, J = 3.9 Hz), 6.68 (1H, d, J = 7.9 Hz), 7.27 (1H, sa), 7.46 (1H, d, J = 8.7 Hz), 7.56 (1H, sa), 7.61 (1H, m), 8.18 (1H, m), 11.37 (1H, s)

355  355
RMN 1H (DMSO-d6): 1,10-1,32 (5H, m), 1,32-1,50 (2H, m), 1,82-1,96 (4H, m), 2,21 (3H, s), 2,35-2,60 (6H, m), 2,84-2,99 (4H, m), 3,42 (1H, m), 3,81 (3H, s), 3,87 (1H, m), 4,56 (1H, d, J = 4,6 Hz), 6,61 (1H, d, J = 7,8 Hz), 6,79 (1H, d, J = 8,6 Hz), 7,09 (1H, d, J = 2,2 Hz), 7,16 (1 H, s.a.), 7,24 (1H, dd, J = 8,6, 2,2 Hz), 7,49 (1H, s.a.), 11,03 (1 H, s)  1H NMR (DMSO-d6): 1.10-1.32 (5H, m), 1.32-1.50 (2H, m), 1.82-1.96 (4H, m), 2.21 (3H, s), 2.35-2.60 (6H, m), 2.84-2.99 (4H, m), 3.42 (1H, m), 3.81 (3H, s), 3.87 (1H, m), 4.56 (1H, d, J = 4.6 Hz), 6.61 (1H, d, J = 7.8 Hz), 6.79 (1H, d, J = 8.6 Hz), 7.09 (1H, d, J = 2.2 Hz), 7.16 (1 H, sa), 7.24 (1H, dd, J = 8.6, 2.2 Hz), 7.49 (1H, sa), 11.03 (1 H, s)

357  357
RMN 1H (DMSO-d6): 1,17 (3H, t, J = 7,4 Hz), 1,21-1,48 (4H, m), 1,84-2,00 (4H, m), 2,55 (2H, q, J = 7,4 Hz), 3,00-3,06 (4H, m), 3,42 (1H, m), 3,69-3,86 (5H, m), 4,58 (1H, d, J = 4,8 Hz), 6,65 (1H, d, J = 7,4 Hz), 6,84-6,90 (2H, m), 7,16 (1H, m), 7,44-7,56 (3H, m), 10,95 (1H, s)  1H NMR (DMSO-d6): 1.17 (3H, t, J = 7.4 Hz), 1.21-1.48 (4H, m), 1.84-2.00 (4H, m), 2.55 (2H, q, J = 7.4 Hz), 3.00-3.06 (4H, m), 3.42 (1H, m), 3.69-3.86 (5H, m) , 4.58 (1H, d, J = 4.8 Hz), 6.65 (1H, d, J = 7.4 Hz), 6.84-6.90 (2H, m), 7.16 ( 1H, m), 7.44-7.56 (3H, m), 10.95 (1H, s)

5 ______________________________________[Tabla 17615 ______________________________________ [Table 1761

Ej  Ex
Datos  Data

370  370
RMN 1H (DMSO-d6): 1,10-1,32 (5H, m), 1,36-1,58 (4H, m), 1,75-1,93 (6H, m), 2,14 (3H, s), 2,22-2,38 (4H, m), 2,40-2,62 (5H, m), 2,65-2,78 (2H, m), 2,87-2,97 (2H, m), 3,20-3,48 (3H, m), 3,87 (1H, m), 4,56 (1H, d, J = 3,9 Hz), 6,67 (1H, d, J = 7,9 Hz), 7,27 (1H, s.a.), 7,42 (1H, d, J = 8,7 Hz), 7,55 (1H, s.a.), 7,62 (1H, m), 8,15 (1H, m), 11,37 (1H, s)  1H NMR (DMSO-d6): 1.10-1.32 (5H, m), 1.36-1.58 (4H, m), 1.75-1.93 (6H, m), 2.14 (3H, s), 2.22-2.38 (4H, m), 2.40-2.62 (5H, m), 2.65-2.78 (2H, m), 2.87-2 , 97 (2H, m), 3.20-3.48 (3H, m), 3.87 (1H, m), 4.56 (1H, d, J = 3.9 Hz), 6.67 ( 1H, d, J = 7.9 Hz), 7.27 (1H, sa), 7.42 (1H, d, J = 8.7 Hz), 7.55 (1H, sa), 7.62 ( 1H, m), 8.15 (1H, m), 11.37 (1H, s)

377  377
RMN 1H (CDCI3): 1,24-1,35 (5H, m), 1,43-1,50 (2H, m), 2,04-2,07 (2H, m), 2,17-2,24 (2H, m), 2,32 (3H, s), 2,36 (3H, s), 2,47 (2H, q, J = 7,1 Hz), 2,58 (4H, s.a.), 2,92-2,94 (4H, m), 3,70 (1H, m), 3,95-3,99 (1H, m), 4,51 (1H, d, J = 7,1 Hz), 5,11 (1H, s.a.), 6,98 (1H, d, J = 8,3 Hz), 7,48-7,52 (3H, m), 10,70 (1H, s.a.).  1H NMR (CDCI3): 1.24-1.35 (5H, m), 1.43-1.50 (2H, m), 2.04-2.07 (2H, m), 2.17-2 , 24 (2H, m), 2.32 (3H, s), 2.36 (3H, s), 2.47 (2H, q, J = 7.1 Hz), 2.58 (4H, sa) , 2.92-2.94 (4H, m), 3.70 (1H, m), 3.95-3.99 (1H, m), 4.51 (1H, d, J = 7.1 Hz ), 5.11 (1H, sa), 6.98 (1H, d, J = 8.3 Hz), 7.48-7.52 (3H, m), 10.70 (1H, sa).

378  378
RMN 1H (CDCI3): 1,23-1,32 (5H, m), 1,45-1,72 (4H, m), 1,92-2,08 (4H, m), 2,17-2,30 (8H, m), 2,45-2,67 (13H, m), 3,15 (2H, m), 3,71-3,73 (1H, m), 3,98 (1H, m), 4,51 (1H, d, J = 7,1 Hz), 5,11 (1H, m), 6,93 (1H, d, J = 8,5 Hz), 7,46-7,52 (3H, m), 10,70 (1H, s.a.).  1H NMR (CDCI3): 1.23-1.32 (5H, m), 1.45-1.72 (4H, m), 1.92-2.08 (4H, m), 2.17-2 , 30 (8H, m), 2.45-2.67 (13H, m), 3.15 (2H, m), 3.71-3.73 (1H, m), 3.98 (1H, m ), 4.51 (1H, d, J = 7.1 Hz), 5.11 (1H, m), 6.93 (1H, d, J = 8.5 Hz), 7.46-7.52 (3H, m), 10.70 (1H, sa).

383  383
rMn 1H (DMSO-d6): 1,17 (3H, t, J = 7,4 Hz), 1,20-1,32 (2H, m), 1,35-1,48 (2H, m), 1,81-1,93 (4H, m), 2,22 (3H, s), 2,40-2,60 (6H, m), 2,94-3,04 (4H, m), 3,36-3,47 (1H, m), 3,76 (3H, s), 3,80-3,93 (1H, m), 4,53 (1H, d, J = 4,3 Hz), 6,58 (1H, d, J = 7,7 Hz), 6,82 (1H, d, J = 8,6 Hz), 6,86 (1H, d, J = 2,0 Hz), 7,10-7,17 (1H, m), 7,37 (1H, dd, J = 2,0, 8,6 Hz), 7,44-7,51 (1H, m), 10,93 (1H, s)  rMn 1H (DMSO-d6): 1.17 (3H, t, J = 7.4 Hz), 1.20-1.32 (2H, m), 1.35-1.48 (2H, m), 1.81-1.93 (4H, m), 2.22 (3H, s), 2.40-2.60 (6H, m), 2.94-3.04 (4H, m), 3, 36-3.47 (1H, m), 3.76 (3H, s), 3.80-3.93 (1H, m), 4.53 (1H, d, J = 4.3 Hz), 6 , 58 (1H, d, J = 7.7 Hz), 6.82 (1H, d, J = 8.6 Hz), 6.86 (1H, d, J = 2.0 Hz), 7.10 -7.17 (1H, m), 7.37 (1H, dd, J = 2.0, 8.6 Hz), 7.44-7.51 (1H, m), 10.93 (1H, s )

387  387
RMN 1H (DMSO-d6): 1,17 (3H, t, J = 7,3 Hz), 1,22-1,52 (4H, m), 1,54-1,78 (4H, m), 1,85-2,03 (6H, m), 2,18 (3H, s), 2,40 (1H, m), 2,56 (2H, q, J = 7,3 Hz), 2,80-2,90 (2H, m), 3,43 (1H, m), 3,82 (1H, m), 4,58 (1H, d, J = 4,7 Hz), 6,70 (1H, d, J = 7,3 H), 7,13 (2H, d, J = 8,5 Hz), 7,19 (1H, a), 7,50 (1H, a), 7,59 (2H, d, J = 8,5 Hz), 11,11 (1H, s)  1H NMR (DMSO-d6): 1.17 (3H, t, J = 7.3 Hz), 1.22-1.52 (4H, m), 1.54-1.78 (4H, m), 1.85-2.03 (6H, m), 2.18 (3H, s), 2.40 (1H, m), 2.56 (2H, q, J = 7.3 Hz), 2.80 -2.90 (2H, m), 3.43 (1H, m), 3.82 (1H, m), 4.58 (1H, d, J = 4.7 Hz), 6.70 (1H, d, J = 7.3 H), 7.13 (2H, d, J = 8.5 Hz), 7.19 (1H, a), 7.50 (1H, a), 7.59 (2H, d, J = 8.5 Hz), 11.11 (1H, s)

Ej  Ex
Datos  Data

388  388
RMN 'H (DMSO-d6): 1,15 (6H, d, J = 6,7 Hz), 1,18-1,33 (2H, m), 1,36-1,59 (4H, m), 1,75-1,91 (6H, m), 2,14 (3H, s), 2,21-2,56 (9H, m), 2,64-2,79 (2H, m), 2,87-2,98 (2H, m), 3,09-3,21 (1H, m), 3,36-3,48 (1H, m), 3,79-3,96 (1H, m), 4,56 (1H, d, J = 3,9 Hz), 6,72 (1H, d, J = 7,3 Hz), 7,22-7,33 (1H, m), 7,42 (1H, d, J = 9,0 Hz), 7,48-7,56 (1H, m), 7,58-7,66 (1H, m), 8,14 (1H, d, J = 2,3 Hz), 11,35 (1H, s).  NMR 'H (DMSO-d6): 1.15 (6H, d, J = 6.7 Hz), 1.18-1.33 (2H, m), 1.36-1.59 (4H, m) , 1.75-1.91 (6H, m), 2.14 (3H, s), 2.21-2.56 (9H, m), 2.64-2.79 (2H, m), 2 , 87-2.98 (2H, m), 3.09-3.21 (1H, m), 3.36-3.48 (1H, m), 3.79-3.96 (1H, m) , 4.56 (1H, d, J = 3.9 Hz), 6.72 (1H, d, J = 7.3 Hz), 7.22-7.33 (1H, m), 7.42 ( 1H, d, J = 9.0 Hz), 7.48-7.56 (1H, m), 7.58-7.66 (1H, m), 8.14 (1H, d, J = 2, 3 Hz), 11.35 (1H, s).

391  391
RmN 1H (CDCl3): 1,26-1,30 (6H, 'm), 1,49-1,76 (6H, m), 1,97-2,01 (2H, m), 2,30 (3H, s), 2,36 (3H, s), 2,48 (2H, q, J = 7,3 Hz), 2,59 (4H, s.a.), 2,91-2,94 (4H, m), 3,73-3,97 (1H, m), 4,61 (1H, d, J = 7,5 Hz), 5,10 (1H, s.a.), 6,96 (1H, d, J = 8,5 Hz), 7,48-7,53 (3H, m), 10,69 (1H, s.a.).  RmN 1H (CDCl3): 1.26-1.30 (6H, 'm), 1.49-1.76 (6H, m), 1.97-2.01 (2H, m), 2.30 ( 3H, s), 2.36 (3H, s), 2.48 (2H, q, J = 7.3 Hz), 2.59 (4H, sa), 2.91-2.94 (4H, m ), 3.73-3.97 (1H, m), 4.61 (1H, d, J = 7.5 Hz), 5.10 (1H, sa), 6.96 (1H, d, J = 8.5 Hz), 7.48-7.53 (3H, m), 10.69 (1H, sa).

392  392
RMN ‘H (CDCl3): 1,26-1,32 (6H, m), 1,54-1,76 (8H, m), 1,92-2,00 (4H, m), 2,28 (3H, s), 2,30 (3H, s), 2,47 (2H, q, J = 7,3 Hz), 2,60-2,66 (11H, m), 3,12-3,15 (2H, m), 3,94-3,97 (1H, m), 4,60 (1H, d, J = 7,3 Hz), 5,10 (1H, s.a.), 6,91 (1H, d, J = 8,5 Hz), 7,41-7,71 (3H, m), 10,69 (1H, s.a.).  NMR 'H (CDCl3): 1.26-1.32 (6H, m), 1.54-1.76 (8H, m), 1.92-2.00 (4H, m), 2.28 ( 3H, s), 2.30 (3H, s), 2.47 (2H, q, J = 7.3 Hz), 2.60-2.66 (11H, m), 3.12-3.15 (2H, m), 3.94-3.97 (1H, m), 4.60 (1H, d, J = 7.3 Hz), 5.10 (1H, sa), 6.91 (1H, d, J = 8.5 Hz), 7.41-7.71 (3H, m), 10.69 (1H, sa).

399  399
RmN ’H (CDCl3): 0,13-0,16 (2H, m), 0,52-0,57 (2H, m), 0,92 (1H, m), 1,24-1,58 (7H, m), 2,03 (2H, m), 2,18 (2H, m), 2,33 (2H, m), 2,49 (2H, q, J = 7,6 Hz), 2,68 (4H, s.a.), 2,98 (4H, m), 3,66 (1H, m), 4,00 (1H, m), 4,56 (1H, d, J = 7,6 Hz), 5,16 (1H, m), 7,34 (1H, d, J = 8,8 Hz), 7,51 (1H, m), 7,62 (1H, dd, J = 8,8, 2,4 Hz), 8,18 (1H, d, J = 2,4 Hz), 10,96 (1H, s.a.).  RmN 'H (CDCl3): 0.13-0.16 (2H, m), 0.52-0.57 (2H, m), 0.92 (1H, m), 1.24-1.58 ( 7H, m), 2.03 (2H, m), 2.18 (2H, m), 2.33 (2H, m), 2.49 (2H, q, J = 7.6 Hz), 2, 68 (4H, sa), 2.98 (4H, m), 3.66 (1H, m), 4.00 (1H, m), 4.56 (1H, d, J = 7.6 Hz), 5.16 (1H, m), 7.34 (1H, d, J = 8.8 Hz), 7.51 (1H, m), 7.62 (1H, dd, J = 8.8, 2, 4 Hz), 8.18 (1H, d, J = 2.4 Hz), 10.96 (1H, sa).

406  406
RMN 1H (CDCl3): 1,29 (3H, t, J = 7,3 Hz), 1,43-1,52 (4H, m), 1,85-1,90 (1H, m), 2,01-2,04 (2H, m), 2,12-2,18 (3H, m), 2,29 (6H, s), 2,46 (2H, q, J = 7,3 Hz), 2,86-2,90 (1H, m), 3,16-3,37 (4H, m), 3,66 (1H, m), 3,97-4,00 (1H, m), 4,53 (1H, d, J = 7,6 Hz), 5,15 (1H, s.a.), 7,11 (1H, d, J = 8,8 Hz), 7,48-7,55 (2H, m), 8,15 (1H, d, J = 2,4 Hz), 10,84 (1H, s.a.).  1H NMR (CDCl3): 1.29 (3H, t, J = 7.3 Hz), 1.43-1.52 (4H, m), 1.85-1.90 (1H, m), 2, 01-2.04 (2H, m), 2.12-2.18 (3H, m), 2.29 (6H, s), 2.46 (2H, q, J = 7.3 Hz), 2 , 86-2.90 (1H, m), 3.16-3.37 (4H, m), 3.66 (1H, m), 3.97-4.00 (1H, m), 4.53 (1H, d, J = 7.6 Hz), 5.15 (1H, sa), 7.11 (1H, d, J = 8.8 Hz), 7.48-7.55 (2H, m) , 8.15 (1H, d, J = 2.4 Hz), 10.84 (1H, sa).

[Tabla 1781[Table 1781

Ej  Ex
Datos  Data

426  426
RMN lH (CDCl3): 1,11 (6H, d, J = 6,3 Hz), 1,24-1,32 (5H, m), 1,39-1,52 (2H, m), 2,05-2,07 (2H, m), 2,20-2,23 (2H, m), 2,32 (3H, s), 2,47 (2H, q, J = 7,3 Hz), 2,70-2,78 (5H, m), 2,94-2,96 (5H, m), 3,66-3,71 (1 H, m), 3,933,98 (1H, m), 4,54 (1H, d, J = 7,1 Hz), 5,19 (1H, s.a.), 6,99 (1H, d, J = 8,5 Hz), 7,44-7,55 (3H, m), 10,68 (1H, s.a.).  1 H NMR (CDCl3): 1.11 (6H, d, J = 6.3 Hz), 1.24-1.32 (5H, m), 1.39-1.52 (2H, m), 2, 05-2.07 (2H, m), 2.20-2.23 (2H, m), 2.32 (3H, s), 2.47 (2H, q, J = 7.3 Hz), 2 , 70-2.78 (5H, m), 2.94-2.96 (5H, m), 3.66-3.71 (1 H, m), 3,933.98 (1H, m), 4, 54 (1H, d, J = 7.1 Hz), 5.19 (1H, sa), 6.99 (1H, d, J = 8.5 Hz), 7.44-7.55 (3H, m ), 10.68 (1H, sa).

459  459
RMN lH (CDCl3): 1,20-1,54 (10H, m), 1,70-2,09 (6H, m), 2,21 (2H, d, J = 11,4 Hz), 2,29 (3H, s), 2,32-2,73 (13H, m), 3,54 (2H, d, J = 11,6 Hz), 3,63-3,75 (1H, m), 3,92-4,40 (1H, m), 4,07 (2H, q, J = 6,9 Hz), 4,52 (1H, d, J = 7,3 Hz), 5,12 (1H, s.a.), 6,84 (1H, d, J = 8,7 Hz), 6,93 (1H, d, J = 2,1 Hz), 7,26 (1H, s), 7,47 (2H, dd, J = 8,5, 2,2 Hz), 10,72 (1H, s).  1 H NMR (CDCl 3): 1.20-1.54 (10H, m), 1.70-2.09 (6H, m), 2.21 (2H, d, J = 11.4 Hz), 2, 29 (3H, s), 2.32-2.73 (13H, m), 3.54 (2H, d, J = 11.6 Hz), 3.63-3.75 (1H, m), 3 , 92-4.40 (1H, m), 4.07 (2H, q, J = 6.9 Hz), 4.52 (1H, d, J = 7.3 Hz), 5.12 (1H, sa), 6.84 (1H, d, J = 8.7 Hz), 6.93 (1H, d, J = 2.1 Hz), 7.26 (1H, s), 7.47 (2H, dd, J = 8.5, 2.2 Hz), 10.72 (1H, s).

466  466
rMn 1H (CDCl3): 1,26-2,74 (38H, m), 3,12-3,15 (2H, m), 4,08 (1H, m), 4,63 (1H, d, J = 6,8 Hz), 5,14 (1H, s.a.), 6,93 (1H, d, J = 8,1 Hz), 7,49-7,54 (3H, m), 10,71 (1H, s.a.).  rMn 1H (CDCl3): 1.26-2.74 (38H, m), 3.12-3.15 (2H, m), 4.08 (1H, m), 4.63 (1H, d, J = 6.8 Hz), 5.14 (1H, sa), 6.93 (1H, d, J = 8.1 Hz), 7.49-7.54 (3H, m), 10.71 (1H , sa).

490  490
RMN lH (CDCl3): 0,96 (3H, t, J = 7,6 Hz), 1,25-2,71 (36H/m), 3,11 - 3,15 (2H, m), 3,95-3,97 (1H, m), 4,61 (1H, d, J = 7,3 Hz), 5,09 (1H, s.a.), 6,91 (1H, d, J = 8,8 Hz), 7,40-7,56 (3H, m), 10,68 (1H, s.a.).  1 H NMR (CDCl 3): 0.96 (3H, t, J = 7.6 Hz), 1.25-2.71 (36H / m), 3.11-3.15 (2H, m), 3, 95-3.97 (1H, m), 4.61 (1H, d, J = 7.3 Hz), 5.09 (1H, sa), 6.91 (1H, d, J = 8.8 Hz ), 7.40-7.56 (3H, m), 10.68 (1H, sa).

491  491
1 H-NMR (CDCla): 0,92 (3H, t, J = 7,3 Hz), 1,26-2,71 (36H, m), 3,12-3,15 (2H, m), 4,11-4,17 (1H, m), 4,64 (1H, d, J = 6,8 Hz), 5,13 (1H, s.a.), 6,93 (1H, d, J = 8,1 Hz), 7,49-7,54 (3H, m), 10,71 (1H, s.a.).  1 H-NMR (CDCla): 0.92 (3H, t, J = 7.3 Hz), 1.26-2.71 (36H, m), 3.12-3.15 (2H, m), 4.11-4.17 (1H, m), 4.64 (1H, d, J = 6.8 Hz), 5.13 (1H, sa), 6.93 (1H, d, J = 8, 1 Hz), 7.49-7.54 (3H, m), 10.71 (1H, sa).

493  493
RMN 1H (CDCl3): 0,96 (6H, d, J = 7,1 Hz), 1,26-1,30 (5H, m), 1,56-2,69 (30H, m), 3,13 (2H, d, J = 10,5 Hz), 3,94 (1H, m), 4,61 (1H, d, J = 7,8 Hz), 5,09 (1H, s.a.), 6,91 (1H, d, J = 8,5 Hz), 7,40 (1H, d, J = 6,6 Hz), 7,48 (1H, s.a.), 7,56 (1H, d, J = 2,7 Hz), 10,67 (1H, s.a.).  1H NMR (CDCl3): 0.96 (6H, d, J = 7.1 Hz), 1.26-1.30 (5H, m), 1.56-2.69 (30H, m), 3, 13 (2H, d, J = 10.5 Hz), 3.94 (1H, m), 4.61 (1H, d, J = 7.8 Hz), 5.09 (1H, sa), 6, 91 (1H, d, J = 8.5 Hz), 7.40 (1H, d, J = 6.6 Hz), 7.48 (1H, sa), 7.56 (1H, d, J = 2 , 7 Hz), 10.67 (1H, sa).

494  494
1 H-NMR (CDCla): 0,95 (6H, d, J = 6,8 Hz), 1,25-3,18 (37H, m), 3,64-3,67 (1H, m), 4,72 (1H, d, J = 7,1 Hz), 5,12 (1H, s.a.), 6,92 (1H, d, J = 8,5 Hz), 7,48-7,54 (3H, m), 10,73 (1H, s.a.).  1 H-NMR (CDCla): 0.95 (6H, d, J = 6.8 Hz), 1.25-3.18 (37H, m), 3.64-3.67 (1H, m), 4.72 (1H, d, J = 7.1 Hz), 5.12 (1H, sa), 6.92 (1H, d, J = 8.5 Hz), 7.48-7.54 (3H , m), 10.73 (1H, sa).

5 ______________________________________[Tabla 17915 ______________________________________ [Table 1791

Ej  Ex
Datos  Data

512  512
RMN 1H (DMSO-d6): 1,19 (3H, t, J = 7,4 Hz), 1,46-1,72 (4H, m), 1,77-1,93 (4H, m), 2,15 (3H, s), 2,20-2,40 (8H, m), 2,44-2,63 (8H, m), 2,97-3,08 (2H, m), 3,34-3,46 (2H, m), 3,88-4,00 (2H, m), 4,11 (1H, m), 6,76 (1H, d, J = 7,5 Hz), 6,94 (1H, d, J = 8,6 Hz), 7,18 (1H, s.a.), 7,34 (1H, m), 7,46 (1H, m), 7,51 (1H, s.a.), 11,00 (1H, s).  1H NMR (DMSO-d6): 1.19 (3H, t, J = 7.4 Hz), 1.46-1.72 (4H, m), 1.77-1.93 (4H, m), 2.15 (3H, s), 2.20-2.40 (8H, m), 2.44-2.63 (8H, m), 2.97-3.08 (2H, m), 3, 34-3.46 (2H, m), 3.88-4.00 (2H, m), 4.11 (1H, m), 6.76 (1H, d, J = 7.5 Hz), 6 , 94 (1H, d, J = 8.6 Hz), 7.18 (1H, sa), 7.34 (1H, m), 7.46 (1H, m), 7.51 (1H, sa) , 11.00 (1H, s).

534  534
RMN 'H (DMSo-d6): 1,18(3H, t, J = 7,4 Hz), 1,39-1,61 (4H, m), 1,78-1,88 (4H, m), 2,14 (3H, s), 2,20-2,39 (8H, m), 2,44-2,62 (10H, m), 2,95-3,06 (4H, m), 3,95 (1H, m), 6,70 (1H, d, J = 7,6 Hz), 6,92 (1H, d, J = 8,6 Hz), 7,15 (1H, s.a.), 7,36 (1H, m), 7,43-7,54 (2H, m), 11,01 (1H, s).  NMR 'H (DMSo-d6): 1.18 (3H, t, J = 7.4 Hz), 1.39-1.61 (4H, m), 1.78-1.88 (4H, m) , 2.14 (3H, s), 2.20-2.39 (8H, m), 2.44-2.62 (10H, m), 2.95-3.06 (4H, m), 3 , 95 (1H, m), 6.70 (1H, d, J = 7.6 Hz), 6.92 (1H, d, J = 8.6 Hz), 7.15 (1H, sa), 7 , 36 (1H, m), 7.43-7.54 (2H, m), 11.01 (1H, s).

544  544
RmN 1H (DMsO-d6): 1,18 (3H, t, j' = 7,4 Hz), 1,48-1,72 (4H, m), 1,77-1,90 (4H, m), 1,90-2,01 (2H, m), 2,14 (3H, s), 2,18 (3H, s), 2,21-2,62 (16H, m), 2,77-2,87 (2H, m), 2,97-3,07 (2H, m), 3,87 (1H, m), 6,72 (1H, m), 6,92 (1H, m), 7,19 (1H, m), 7,28 (1H, m), 7,46-7,56 (2H, m), 11,02 (1H, s)  RmN 1H (DMsO-d6): 1.18 (3H, t, j '= 7.4 Hz), 1.48-1.72 (4H, m), 1.77-1.90 (4H, m) , 1.90-2.01 (2H, m), 2.14 (3H, s), 2.18 (3H, s), 2.21-2.62 (16H, m), 2.77-2 , 87 (2H, m), 2.97-3.07 (2H, m), 3.87 (1H, m), 6.72 (1H, m), 6.92 (1H, m), 7, 19 (1H, m), 7.28 (1H, m), 7.46-7.56 (2H, m), 11.02 (1H, s)

545  545
rMn 1H (DMsO-d6): 1,18 (3H, t, J = 7,4 Hz), 1,55-1,69 (2H, m), 1,83-1,92 (2H, m), 2,22 (3H, s), 2,40-2,50 (4H, m), 2,57 (2H, q, J = 7,4 Hz), 2,98-3,14 (4H, m), 3,36-4,48 (2H, m), 3,88-3,98 (2H, m), 4,06 (1H, m), 6,78 (1H, m), 6,84-6,94 (2H, m), 7,18 (1H, m), 7,40-7,54 (3H, m), 10,91 (1H, s)  rMn 1H (DMsO-d6): 1.18 (3H, t, J = 7.4 Hz), 1.55-1.69 (2H, m), 1.83-1.92 (2H, m), 2.22 (3H, s), 2.40-2.50 (4H, m), 2.57 (2H, q, J = 7.4 Hz), 2.98-3.14 (4H, m) , 3.36-4.48 (2H, m), 3.88-3.98 (2H, m), 4.06 (1H, m), 6.78 (1H, m), 6.84-6 , 94 (2H, m), 7.18 (1H, m), 7.40-7.54 (3H, m), 10.91 (1H, s)

546  546
rMn 1H (DMSO-d6): 1,18 (3H, t, J = 7,4 Hz), 1,42-1,68 (4H, m), 1,78-1,92 (4H, m), 2,13 (3H, s), 2,20-2,64 (13H, m), 3,26-3,46 (2H, m), 3,57-3,67 (2H, m), 3,89-3,97 (2H, m), 4,05 (1H, m), 6,78 (1H, m), 6,85-6,93 (2H, m), 7,17 (1H, m), 7,42-7,53 (3H, m), 10,89 (1H, s)  rMn 1H (DMSO-d6): 1.18 (3H, t, J = 7.4 Hz), 1.42-1.68 (4H, m), 1.78-1.92 (4H, m), 2.13 (3H, s), 2.20-2.64 (13H, m), 3.26-3.46 (2H, m), 3.57-3.67 (2H, m), 3, 89-3.97 (2H, m), 4.05 (1H, m), 6.78 (1H, m), 6.85-6.93 (2H, m), 7.17 (1H, m) , 7.42-7.53 (3H, m), 10.89 (1H, s)

547  547
rMn 1H (DMSO-d6): 1,19 (3H, t, J = 7,4 Hz), 1,44-1,72 (4H, m), 1,74-1,90 (4H, m), 2,14 (3H, s), 2,18-2,64 (13H, m), 3,18-3,44 (4H, m), 3,81 (3H, s), 3,86-3,96 (2H, m), 4,10 (1H, m), 6,77 (1H, m), 6,82 (1H, m), 7,03 (1H, m), 7,20 (1H, m), 7,25 (1H, m), 7,52 (1H, m), 11,01 (1H, m)  rMn 1H (DMSO-d6): 1.19 (3H, t, J = 7.4 Hz), 1.44-1.72 (4H, m), 1.74-1.90 (4H, m), 2.14 (3H, s), 2.18-2.64 (13H, m), 3.18-3.44 (4H, m), 3.81 (3H, s), 3.86-3, 96 (2H, m), 4.10 (1H, m), 6.77 (1H, m), 6.82 (1H, m), 7.03 (1H, m), 7.20 (1H, m ), 7.25 (1H, m), 7.52 (1H, m), 11.01 (1H, m)

Ej  Ex
Datos  Data

565  565
RMN 'H (DMSO-ds): 1,17 (3H, t, J = 7,2 Hz), 1,22-1,48 (4H, m), 1,86-1,98 (4H, m), 2,26 (3H, s), 2,47-2,58 (6H, m), 3,01-3,14 (4H, m), 3,14-3,60 (1H, m), 3,82-3,87 (1H, m), 4,59 (1H, s.a.), 6,60 (1H, s), 6,65 (1H, d, J = 7,6 Hz), 6,83-6,90 (2H, m), 7,12-7,19 (1H, m), 7,44-7,54 (3H, m), 10,95 (1H, s) XRD: 12,6, 17,6, 22,2, 23,5, 24,2  1 H NMR (DMSO-ds): 1.17 (3H, t, J = 7.2 Hz), 1.22-1.48 (4H, m), 1.86-1.98 (4H, m) , 2.26 (3H, s), 2.47-2.58 (6H, m), 3.01-3.14 (4H, m), 3.14-3.60 (1H, m), 3 , 82-3.87 (1H, m), 4.59 (1H, sa), 6.60 (1H, s), 6.65 (1H, d, J = 7.6 Hz), 6.83- 6.90 (2H, m), 7.12-7.19 (1H, m), 7.44-7.54 (3H, m), 10.95 (1H, s) XRD: 12.6, 17 , 6, 22.2, 23.5, 24.2

566  566
RMN ‘H (DMSO-d6): 1,17(3H,t,J=7,6 Hz), 1,22-1,62(6H,m), 1,78-2,02 (6H, m), 2,20 (3H, s), 2,24-2,76 (14H, m), 3,10-3,88 (4H, m), 6,55 (1H, s), 6,66 (1H, d, J = 6,0 Hz), 6,83-6,90 (2H, m), 7,12-7,19 (1H, m), 7,44-7,54 (3H, m), 10,93 (1 H, s) XRD: 5,7, 18,0, 18,9, 20,1, 20,2  NMR 'H (DMSO-d6): 1.17 (3H, t, J = 7.6 Hz), 1.22-1.62 (6H, m), 1.78-2.02 (6H, m) , 2.20 (3H, s), 2.24-2.76 (14H, m), 3.10-3.88 (4H, m), 6.55 (1H, s), 6.66 (1H , d, J = 6.0 Hz), 6.83-6.90 (2H, m), 7.12-7.19 (1H, m), 7.44-7.54 (3H, m), 10.93 (1 H, s) XRD: 5.7, 18.0, 18.9, 20.1, 20.2

567  567
RMN ’H (DMSO-d6): 1,13 (6H, d, J = 6,8 Hz), 1,21-1,48 (4H, m), 1,84-1,98 (4H, m), 2,26 (3H, s), 2,48-2,56 (4H, m), 3,03-3,18 (5H, m), 3,37-3,47 (1H, m), 3,75-3,86 (1H, m), 4,58 (1H, s.a.), 6,59 (1H, s), 6,70 (1H, d, J = 7,6 Hz), 6,84-6,90 (2H, m), 7,15-7,20 (1H, m), 7,42-7,47 (1H, m), 7,48-7,54 (2H, m), 10,92 (1H, s) XRD: 11,0, 11,2, 17,3, 17,5, 22,5  1 H NMR (DMSO-d6): 1.13 (6H, d, J = 6.8 Hz), 1.21-1.48 (4H, m), 1.84-1.98 (4H, m) , 2.26 (3H, s), 2.48-2.56 (4H, m), 3.03-3.18 (5H, m), 3.37-3.47 (1H, m), 3 , 75-3.86 (1H, m), 4.58 (1H, sa), 6.59 (1H, s), 6.70 (1H, d, J = 7.6 Hz), 6.84- 6.90 (2H, m), 7.15-7.20 (1H, m), 7.42-7.47 (1H, m), 7.48-7.54 (2H, m), 10, 92 (1H, s) XRD: 11.0, 11.2, 17.3, 17.5, 22.5

568  568
RMN lH (DMSO-d6): 1,14-1,34 (5H, m), 1,36-1,61 (4H, m), 1,78-1,94 (6H, m), 2,22 (3H, s), 2,28-2,65 (12H, m), 2,68-2,80 (2H, m), 2,89-3,01 (2H, m), 3,36-3,47 (1H, m), 3,81-3,94 (1H, m), 6,55 (1H, s), 6,70 (1H, d, J = 7,6 Hz), 7,28-7,32 (1H, m), 7,43 (1H, d, J = 8,8 Hz), 7,54-7,64 (2H, m), 8,17 (1H, d, J = 2,4 Hz), 11,39 (1H, s) XRD: 8,4, 8,5, 20,2, 20,3, 20,4  1 H NMR (DMSO-d6): 1.14-1.34 (5H, m), 1.36-1.61 (4H, m), 1.78-1.94 (6H, m), 2.22 (3H, s), 2.28-2.65 (12H, m), 2.68-2.80 (2H, m), 2.89-3.01 (2H, m), 3.36-3 , 47 (1H, m), 3.81-3.94 (1H, m), 6.55 (1H, s), 6.70 (1H, d, J = 7.6 Hz), 7.28- 7.32 (1H, m), 7.43 (1H, d, J = 8.8 Hz), 7.54-7.64 (2H, m), 8.17 (1H, d, J = 2, 4 Hz), 11.39 (1H, s) XRD: 8.4, 8.5, 20.2, 20.3, 20.4

569  569
RMN lH (DMSO-d6): 1,17 (3H, t, J = 7,6 Hz), 1,21-1,35 (2H, m), 1,36-1,49 (2H, m), 1,50-1,63 (2H, m), 1,80-1,98 (6H, m), 2,24 (3H, s), 2,25 (3H, s), 2,30-2,70 (14H, m), 2,98-3,10 (2H, m), 3,37-3,48 (1H, m), 3,80-3,92 (1H, m), 6,57 (1H, s), 6,65 (1H, d, J = 7,6 Hz), 6,93 (1H, d, J = 8,8 Hz), 7,14-7,22 (1H, m), 7,37 (1H, dd, J = 2,4, 8,8 Hz), 7,46-7,53 (2H, m), 11,03 (1H, s) XRD: 9,5, 18,4, 19,0, 19,4, 23,9  1 H NMR (DMSO-d6): 1.17 (3H, t, J = 7.6 Hz), 1.21-1.35 (2H, m), 1.36-1.49 (2H, m), 1.50-1.63 (2H, m), 1.80-1.98 (6H, m), 2.24 (3H, s), 2.25 (3H, s), 2.30-2, 70 (14H, m), 2.98-3.10 (2H, m), 3.37-3.48 (1H, m), 3.80-3.92 (1H, m), 6.57 ( 1H, s), 6.65 (1H, d, J = 7.6 Hz), 6.93 (1H, d, J = 8.8 Hz), 7.14-7.22 (1H, m), 7.37 (1H, dd, J = 2.4, 8.8 Hz), 7.46-7.53 (2H, m), 11.03 (1H, s) XRD: 9.5, 18.4 , 19.0, 19.4, 23.9

[Tabla 181][Table 181]

Ej  Ex
Datos  Data

570  570
RMN lH (DMSO-d6): 1,15 (6H, d, J = 6,4 Hz), 1,18-1,32 (2H, m), 1,37-1,58 (4H, m), 1,78-1,91 (6H, m), 2,21 (3H, s), 2,28-2,80 (12H, m), 2,89-2,98 (2H, m), 3,10-3,60 (2H, m), 3,82-3,94 (1H, m), 6,55 (1H, s), 6,75 (1H, d, J = 8,0 Hz), 7,28-7,35 (1H, m), 7,43 (1H, d, J = 8,4 Hz), 7,50-7,57 (1H, m), 7,59-7,65 (1 H, m), 8,15 (1H, d, J = 2,8 Hz), 11,36 (1H, s) XRD: 17,9, 18,3, 18,4, 18,9, 19,0  1 H NMR (DMSO-d6): 1.15 (6H, d, J = 6.4 Hz), 1.18-1.32 (2H, m), 1.37-1.58 (4H, m), 1.78-1.91 (6H, m), 2.21 (3H, s), 2.28-2.80 (12H, m), 2.89-2.98 (2H, m), 3, 10-3.60 (2H, m), 3.82-3.94 (1H, m), 6.55 (1H, s), 6.75 (1H, d, J = 8.0 Hz), 7 , 28-7.35 (1H, m), 7.43 (1H, d, J = 8.4 Hz), 7.50-7.57 (1H, m), 7.59-7.65 (1 H, m), 8.15 (1H, d, J = 2.8 Hz), 11.36 (1H, s) XRD: 17.9, 18.3, 18.4, 18.9, 19.0

571  571
RMN lH (DMSO-d6): 1,12-1,20 (6H, m), 1,33-1,45 (2H, m), 1,59-1,89 (10H, m), 2,23 (3H, s), 2,26 (3H, s), 2,302,73 (13H, m), 2,97-3,07 (2H, m), 3,79-3,91 (1H, m), 4,03-4,14 (1H, m), 6,57 (1H, s), 6,72 (1H, d, J = 7,6 Hz), 6,92 (1H, d, J = 8,4 Hz), 7,14-7,19 (1H, m), 7,28 (1H, dd, J = 2,4, 8,4 Hz), 7,46-7,51 (1H, m), 7,56 (1H, d, J = 2,4 Hz), 11,01 (1H, s) XRD: 7,9, 15,1, 19,4, 19,9, 20,3  1 H NMR (DMSO-d6): 1.12-1.20 (6H, m), 1.33-1.45 (2H, m), 1.59-1.89 (10H, m), 2.23 (3H, s), 2.26 (3H, s), 2.302.73 (13H, m), 2.97-3.07 (2H, m), 3.79-3.91 (1H, m), 4.03-4.14 (1H, m), 6.57 (1H, s), 6.72 (1H, d, J = 7.6 Hz), 6.92 (1H, d, J = 8, 4 Hz), 7.14-7.19 (1H, m), 7.28 (1H, dd, J = 2.4, 8.4 Hz), 7.46-7.51 (1H, m), 7.56 (1H, d, J = 2.4 Hz), 11.01 (1H, s) XRD: 7.9, 15.1, 19.4, 19.9, 20.3

572  572
RMN lH (DMSO-d6): 1,04 (6H, d, J = 6,8 Hz), 1,17 (3H, t, J = 7,2 Hz), 1,21-1,35 (2H, m), 1,36-1,50 (2H, m), 1,84-1,97 (4H, m), 2,27 (3H, s), 2,55 (2H, q, J = 7,2 Hz), 2,62-2,70 (4H, m), 2,72-2,86 (5H, m), 3,20-3,55 (2H, m), 3,80-3,91 (1H, m), 6,57 (1H, s), 6,66 (1H, d, J = 7,6 Hz), 6,94 (1H, d, J = 8,4 Hz), 7,15-7,21 (1H, m), 7,39 (1H, dd, J = 2,4, 8,4 Hz), 7,46-7,52 (2H, m), 11,02 (1H, s) XRD: 10,1, 14,5, 17,9, 22,1, 23,0  1 H NMR (DMSO-d6): 1.04 (6H, d, J = 6.8 Hz), 1.17 (3H, t, J = 7.2 Hz), 1.21-1.35 (2H, m), 1.36-1.50 (2H, m), 1.84-1.97 (4H, m), 2.27 (3H, s), 2.55 (2H, q, J = 7, 2 Hz), 2.62-2.70 (4H, m), 2.72-2.86 (5H, m), 3.20-3.55 (2H, m), 3.80-3.91 (1H, m), 6.57 (1H, s), 6.66 (1H, d, J = 7.6 Hz), 6.94 (1H, d, J = 8.4 Hz), 7.15 -7.21 (1H, m), 7.39 (1H, dd, J = 2.4, 8.4 Hz), 7.46-7.52 (2H, m), 11.02 (1H, s ) XRD: 10.1, 14.5, 17.9, 22.1, 23.0

573  573
RMN lH (DMSO-d6): 1,14-1,22 (6H, m), 1,43-1,65 (8H, m), 1,79-1,90 (4H, m), 2,25 (3H, s), 2,27 (3H, s), 2,302,70 (14H, m), 2,99-3,09 (2H, m), 3,86-3,98 (1H, m), 6,57 (2H, s), 6,62 (1H, d, J = 7,6 Hz), 6,93 (1H, d, J = 8,4 Hz), 7,15-7,21 (1H, m), 7,36 (1H, dd, J = 2,0, 8,4 Hz), 7,47-7,52 (2H, m), 11,03 (1H, s) XRD: 6,3, 13,7, 16,7, 17,7, 18,4  1 H NMR (DMSO-d6): 1.14-1.22 (6H, m), 1.43-1.65 (8H, m), 1.79-1.90 (4H, m), 2.25 (3H, s), 2.27 (3H, s), 2.302.70 (14H, m), 2.99-3.09 (2H, m), 3.86-3.98 (1H, m), 6.57 (2H, s), 6.62 (1H, d, J = 7.6 Hz), 6.93 (1H, d, J = 8.4 Hz), 7.15-7.21 (1H , m), 7.36 (1H, dd, J = 2.0, 8.4 Hz), 7.47-7.52 (2H, m), 11.03 (1H, s) XRD: 6.3 , 13.7, 16.7, 17.7, 18.4

5 ______________________________________[Tabla 18215 ______________________________________ [Table 1821

Ej  Ex
Datos  Data

574  574
RMN lH (DMSO-d6): 1,19 (3H, t, J = 7,6 Hz), 1,50-1,72 (4H, m), 1,80-1,93 (4H, m), 2,21 (3H, s), 2,24 (3H, s), 2,48-2,65 (13H, m), 2,99-3,08 (2H, m), 3,30-3,50 (2H, m), 3,90-4,00 (2H, m), 4,05-4,18 (1H, m), 6,56 (1H, s), 6,78 (1H, d, J = 7,6 Hz), 6,95 (1H, d, J = 8,4 Hz), 7,17-7,24 (1H, m), 7,34 (1H, dd, J = 2,4, 8,4 Hz), 7,46 (1H, d, J = 2,4 Hz), 7,49-7,55 (1H, m), 11,01 (1H, s) XRD: 11,5, 17,7, 19,1, 21,4, 22,3  1 H NMR (DMSO-d6): 1.19 (3H, t, J = 7.6 Hz), 1.50-1.72 (4H, m), 1.80-1.93 (4H, m), 2.21 (3H, s), 2.24 (3H, s), 2.48-2.65 (13H, m), 2.99-3.08 (2H, m), 3.30-3, 50 (2H, m), 3.90-4.00 (2H, m), 4.05-4.18 (1H, m), 6.56 (1H, s), 6.78 (1H, d, J = 7.6 Hz), 6.95 (1H, d, J = 8.4 Hz), 7.17-7.24 (1H, m), 7.34 (1H, dd, J = 2.4 , 8.4 Hz), 7.46 (1H, d, J = 2.4 Hz), 7.49-7.55 (1H, m), 11.01 (1H, s) XRD: 11.5, 17.7, 19.1, 21.4, 22.3

575  575
RMN lH (DMSO-d6): 1,17-1,33 (2H, m), 1,43-1,63 (4H, m), 1,79-1,94 (6H, m), 2,25 (3H, s), 2,26 (3H, s), 2,302,69 (11H, m), 2,99-3,89 (5H, m), 5,75 (2H, s), 6,95 (1H, d, J = 8,4 Hz), 7,07 (1H, d, J = 8,4 Hz), 7,31-7,35 (2H, m), 7,47-7,49 (1H, m), 7,54 (1H, s), 11,19 (1H, s) XRD: 5,6, 8,0, 17,8, 18,6, 24,0  1 H NMR (DMSO-d6): 1.17-1.33 (2H, m), 1.43-1.63 (4H, m), 1.79-1.94 (6H, m), 2.25 (3H, s), 2.26 (3H, s), 2.302.69 (11H, m), 2.99-3.89 (5H, m), 5.75 (2H, s), 6.95 ( 1H, d, J = 8.4 Hz), 7.07 (1H, d, J = 8.4 Hz), 7.31-7.35 (2H, m), 7.47-7.49 (1H , m), 7.54 (1H, s), 11.19 (1H, s) XRD: 5.6, 8.0, 17.8, 18.6, 24.0

576  576
RMN lH (DMSO-d6): 1,18 (3H, t, J = 7,2 Hz), 1,44-1,72 (4H, m), 1,80-1,97 (4H, m), 2,21 (3H, s), 2,25-2,72 (13H, m), 3,30-3,70 (4H, m), 3,90-3,98 (2H, m), 3,99-4,11 (1H, m), 6,55 (1H, s), 6,78 (1H, d, J = 7,6 Hz), 6,856,93 (2H, m), 7,14-7,21 (1H, m), 7,43-7,52 (3H, m), 10,89 (1H, s) XRD: 8,9, 16,6, 13,1, 20,1, 22,4  1 H NMR (DMSO-d6): 1.18 (3H, t, J = 7.2 Hz), 1.44-1.72 (4H, m), 1.80-1.97 (4H, m), 2.21 (3H, s), 2.25-2.72 (13H, m), 3.30-3.70 (4H, m), 3.90-3.98 (2H, m), 3, 99-4.11 (1H, m), 6.55 (1H, s), 6.78 (1H, d, J = 7.6 Hz), 6.856.93 (2H, m), 7.14-7 , 21 (1H, m), 7.43-7.52 (3H, m), 10.89 (1H, s) XRD: 8.9, 16.6, 13.1, 20.1, 22.4

Ej  Ex
Datos  Data

XRD: 8,9, 16,6, 13,1, 20,1, 22,4  XRD: 8.9, 16.6, 13.1, 20.1, 22.4

577  577
RMN 'H (DMSO-d6): 1,19 (3H, t, J = 7,6 Hz), 1,49-1,70 (4H, m), 1,77-1,91 (4H, m), 2,21 (3H, s), 2,26-2,70 (13H, m), 3,29-3,43 (4H, m), 3,81 (3H, s), 3,88-3,97 (2H, m), 4,06-4,18 (1H, m), 6,55 (1H, s), 6,77 (1H, d, J = 7,6 Hz), 6,82 (1H, d, J = 8,4 Hz), 7,03 (1H, d, J = 2,0 Hz), 7,18-7,29 (2H, m), 7,49-7,55 (1H, m), 11,01 (1H, s) XRD: 11,6, 17,7, 19,2, 21,5, 22,4  1 H NMR (DMSO-d6): 1.19 (3H, t, J = 7.6 Hz), 1.49-1.70 (4H, m), 1.77-1.91 (4H, m) , 2.21 (3H, s), 2.26-2.70 (13H, m), 3.29-3.43 (4H, m), 3.81 (3H, s), 3.88-3 , 97 (2H, m), 4.06-4.18 (1H, m), 6.55 (1H, s), 6.77 (1H, d, J = 7.6 Hz), 6.82 ( 1H, d, J = 8.4 Hz), 7.03 (1H, d, J = 2.0 Hz), 7.18-7.29 (2H, m), 7.49-7.55 (1H , m), 11.01 (1H, s) XRD: 11.6, 17.7, 19.2, 21.5, 22.4

578  578
RMN ‘H (DMSO-d6): 1,15 (6H, d, J = 6,8 Hz), 1,42-1,70 (4H, m), 1,78-1,92 (4H, m), 2,21 (3H, s), 2,26-2,72 (11H, m), 3,08-3,21 (1H, m), 3,34-3,48 (2H, m), 3,56-3,69 (2H, m), 3,87-3,98 (2H, m), 4,00-4,13 (1H, m), 6,55 (1H, s), 6,83 (1H, d, J = 7,6 Hz), 6,85-6,93 (2H, m), 7,15-7,22 (1H, m), 7,41-7,51 (3H, m), 10,87 (1H, s) XRD: 10,3, 16,9, 19,3, 19,9, 21,1  1 H NMR (DMSO-d6): 1.15 (6H, d, J = 6.8 Hz), 1.42-1.70 (4H, m), 1.78-1.92 (4H, m) , 2.21 (3H, s), 2.26-2.72 (11H, m), 3.08-3.21 (1H, m), 3.34-3.48 (2H, m), 3 , 56-3.69 (2H, m), 3.87-3.98 (2H, m), 4.00-4.13 (1H, m), 6.55 (1H, s), 6.83 (1H, d, J = 7.6 Hz), 6.85-6.93 (2H, m), 7.15-7.22 (1H, m), 7.41-7.51 (3H, m ), 10.87 (1H, s) XRD: 10.3, 16.9, 19.3, 19.9, 21.1

[Tabla 1831[Table 1831

Ej  Ex
Datos  Data

579  579
RMN ’H (DMSO-d6): 1,19 (3H, t, J = 7,6 Hz), 1,58-1,72 (2H, m), 1,84-1,94 (2H, m), 2,26 (3H, s), 2,45-2,64 (6H, m), 2,91-3,02 (4H, m), 3,33-3,49 (2H, m), 3,91-3,99 (2H, m), 4,02-4,14 (1H, m), 6,59 (1H, s), 6,86-6,92 (1H, m), 6,93-7,04 (2H, m), 7,24-7,30 (1H, m), 7,52-7,59 (1H, m), 7,88 (1H, dd, J = 2,4, 16 Hz), 11,18 (1H, s) XRD: 5,7, 11,5, 18,2, 23,6, 23,9  1 H NMR (DMSO-d6): 1.19 (3H, t, J = 7.6 Hz), 1.58-1.72 (2H, m), 1.84-1.94 (2H, m) , 2.26 (3H, s), 2.45-2.64 (6H, m), 2.91-3.02 (4H, m), 3.33-3.49 (2H, m), 3 , 91-3.99 (2H, m), 4.02-4.14 (1H, m), 6.59 (1H, s), 6.86-6.92 (1H, m), 6.93 -7.04 (2H, m), 7.24-7.30 (1H, m), 7.52-7.59 (1H, m), 7.88 (1H, dd, J = 2.4, 16 Hz), 11.18 (1H, s) XRD: 5.7, 11.5, 18.2, 23.6, 23.9

580  580
RMN lH (DMSO-d6): 1,16 (6H, d, J = 6,8 Hz), 1,57-1,70 (2H, m), 1,80-1,89 (2H, m), 2,29 (3H, s), 2,48-2,60 (4H, m), 2,89-3,00 (4H, m), 3,10-3,22 (1H, m), 3,30-3,42 (2H, m), 3,81 (3H, s), 3,87-3,96 (2H, m), 4,06-4,19 (1H, m), 6,58 (1H, s), 6,78-6,86 (2H, m), 7,04 (1H, d, J = 2,0 Hz), 7,19-7,30 (2H, m), 7,46-7,53 (1H, m), 11,00 (1H, s) XRD: 8,2, 11,8, 15,9, 18,0, 21,3  1 H NMR (DMSO-d6): 1.16 (6H, d, J = 6.8 Hz), 1.57-1.70 (2H, m), 1.80-1.89 (2H, m), 2.29 (3H, s), 2.48-2.60 (4H, m), 2.89-3.00 (4H, m), 3.10-3.22 (1H, m), 3, 30-3.42 (2H, m), 3.81 (3H, s), 3.87-3.96 (2H, m), 4.06-4.19 (1H, m), 6.58 ( 1H, s), 6.78-6.86 (2H, m), 7.04 (1H, d, J = 2.0 Hz), 7.19-7.30 (2H, m), 7.46 -7.53 (1H, m), 11.00 (1H, s) XRD: 8.2, 11.8, 15.9, 18.0, 21.3

581  581
RMN lH (DMSO-d6): 1,15 (6H, d, J = 6,4 Hz), 1,55-1,70 (2H, m), 1,81-1,91 (2H, m), 2,27 (3H, s), 2,47-2,55 (4H, m), 3,01-3,22 (5H, m), 3,34-3,50 (2H, m), 3,88-3,98 (2H, m), 4,00-4,13 (1H, m), 6,59 (1H, s), 6,83 (1H, d, J = 7,2 Hz), 6,86-6,92 (2H, m), 7,16-7,23 (1H, m), 7,43-7,51 (3H, m), 10,89 (1H, s) XRD: 11,1, 17,2, 19,5, 20,1, 20,5  1 H NMR (DMSO-d6): 1.15 (6H, d, J = 6.4 Hz), 1.55-1.70 (2H, m), 1.81-1.91 (2H, m), 2.27 (3H, s), 2.47-2.55 (4H, m), 3.01-3.22 (5H, m), 3.34-3.50 (2H, m), 3, 88-3.98 (2H, m), 4.00-4.13 (1H, m), 6.59 (1H, s), 6.83 (1H, d, J = 7.2 Hz), 6 , 86-6.92 (2H, m), 7.16-7.23 (1H, m), 7.43-7.51 (3H, m), 10.89 (1H, s) XRD: 11, 1, 17.2, 19.5, 20.1, 20.5

582  582
RMN lH (DMSO-d6): 1,19 (3H, t, J = 7,2 Hz), 1,43-1,57 (2H, m), 1,58-1,71 (2H, m), 1,74-1,91 (4H, m), 2,03-2,16 (2H, m), 2,20-2,30 (8H, m), 2,53-2,69 (5H, m), 2,74-2,84 (4H, m), 2,87-2,98 (2H, m), 3,34-3,45 (2H, m), 3,893,99 (2H, m), 4,04-4,17 (1H, m), 6,52 (1H, s), 6,79 (1H, d, J = 7,6 Hz), 6,96 (1H, d, J = 8,4 Hz), 7,18-7,23 (1H, m), 7,36 (1H, dd, J = 2,4, 8,4 Hz), 7,46 (1H, d, J = 2,4 Hz), 7,49-7,54 (1H, m), 11,01 (1H, s) XRD: 8,1, 13,1, 15,1, 17,5, 23,8  1 H NMR (DMSO-d6): 1.19 (3H, t, J = 7.2 Hz), 1.43-1.57 (2H, m), 1.58-1.71 (2H, m), 1.74-1.91 (4H, m), 2.03-2.16 (2H, m), 2.20-2.30 (8H, m), 2.53-2.69 (5H, m ), 2.74-2.84 (4H, m), 2.87-2.98 (2H, m), 3.34-3.45 (2H, m), 3.893.99 (2H, m), 4.04-4.17 (1H, m), 6.52 (1H, s), 6.79 (1H, d, J = 7.6 Hz), 6.96 (1H, d, J = 8, 4 Hz), 7.18-7.23 (1H, m), 7.36 (1H, dd, J = 2.4, 8.4 Hz), 7.46 (1H, d, J = 2.4 Hz), 7.49-7.54 (1H, m), 11.01 (1H, s) XRD: 8.1, 13.1, 15.1, 17.5, 23.8

5 Las Tablas 184 a 201 muestran las estructuras de otros compuestos de la presente invencion. Estos compuestos se sintetizaron, o pueden sintetizarse, usando los procesos de preparacion anteriores, procesos descritos en los ejemplos, procesos obvios para aquellos expertos en la materia, o procesos modificados de los mismos.5 Tables 184 to 201 show the structures of other compounds of the present invention. These compounds were synthesized, or can be synthesized, using the above preparation processes, processes described in the examples, processes obvious to those skilled in the art, or modified processes thereof.

Los significados de los sfmbolos en las tablas son los siguientes.The meanings of the symbols in the tables are as follows.

10 N°: Compuesto N°.10 No.: Compound No.

-R11 y -R12: sustituyentes en las formulas generales. cBu: ciclobutilo, 2py: 2-piridilo, 3Py: 3-piridilo, 4Py: 4-piridilo.-R11 and -R12: substituents in the general formulas. cBu: cyclobutyl, 2py: 2-pyridyl, 3Py: 3-pyridyl, 4Py: 4-pyridyl.

imagen142image142

No  Do not
-R11 -R12  -R11 -R12

A61  A61
-H -Et  -H -Et

A62  A62
-Me -Et  -Me -Et

A63  A63
-Et -Et  -Et -Et

A64  A64
-nPr -Et  -nPr -Et

A65  A65
-iPr -Et  -iPr -Et

A66#  A66 #
-cPr -Et  -cPr -Et

A67#  A67 #
-cBu -Et  -cBu -Et

A68#  A68 #
-Et    -Et

A69#  A69 #
^3 -Et  ^ 3 -Et

A70#  A70 #
-O -Et  -OR -Et

A71  A71
-CF3 -Et  -CF3 -Et

A72#  A72 #
-CN -Et  -CN -Et

A73#  A73 #
-Ph -Et  -Ph -Et

A74  A74
-OMe -Et  -OMe -Et

A75  A75
-OEt -Et  -OEt -Et

A76  A76
-OnPr -Et  -OnPr -Et

All  All
-OiPr -Et  -OiPr -Et

Aim  Aim
-OcPr -Et  -OcPr -Et

A79#  A79 #
-OCH2cPr -Et  -OCH2cPr -Et

A80  A80
-OCHCF2 -Et  -OCHCF2 -Et

A81  A81
-ocf3 -Et  -ocf3 -Et

A82  A82
-och2cf3 -Et  -och2cf3 -Et

A83  A83
-och2ch2f -Et  -och2ch2f -Et

am#  A.M#
-OCH2CH2OMe -Et  -OCH2CH2OMe -Et

A85#  A85 #
-OCH2CH2NMe2 -Et  -OCH2CH2NMe2 -Et

A86  A86
-F -Et  -F -Et

A87  A87
-Cl -Et  -Cl -Et

A88  A88
-Br -Et  -Br -Et

A89  A89
-I -Et  -I -Et

A90a#  A90a #
-2Py -Et  -2Py -Et

A90b#  A90b #
-3Py -Et  -3Py -Et

A90c#  A90c #
-4Py -Et  -4Py -Et

No  Do not
-R11 -R12  -R11 -R12

A31#  A31 #
-H -Me  -H -Me

A32#  A32 #
-Me -Me  -Me -Me

A33#  A33 #
-Et -Me  -Et -Me

A34#  A34 #
-nPr -Me  -nPr -Me

A35#  A35 #
-iPr -Me  -iPr -Me

A3 6#  A3 6 #
-cPr -Me  -cPr -Me

A37#  A37 #
-cBu -Me  -cBu -Me

A3 8#  A3 8 #
-0 -Me  -0 -Me

A3 9#  A3 9 #
-Me    -I

A40#  A40 #
K3° -Me  K3 ° -Me

A41#  A41 #
-CF3 -Me  -CF3 -Me

A42#  A42 #
-CN -Me  -CN -Me

A43#  A43 #
-Ph -Me  -Ph -Me

A44#  A44 #
-OMe -Me  -OMe -Me

A45#  A45 #
-OEt -Me  -OEt -Me

A46#  A46 #
-OnPr -Me  -OnPr -Me

A47#  A47 #
-OiPr -Me  -OiPr -Me

A48#  A48 #
-OcPr -Me  -OcPr -Me

A49#  A49 #
-OCH2cPr -Me  -OCH2cPr -Me

A50#  A50 #
-ochcf2 -Me  -ochcf2 -Me

A51#  A51 #
-ocf3 -Me  -ocf3 -Me

A52#  A52 #
-och2cf3 -Me  -och2cf3 -Me

A53#  A53 #
-och2ch2f -Me  -och2ch2f -Me

A54#  A54 #
-OCH2CH2OMe -Me  -OCH2CH2OMe -Me

A55#  A55 #
-OCH2CH2NMe2 -Me  -OCH2CH2NMe2 -Me

A56#  A56 #
-F -Me  -F -Me

A57#  A57 #
-Cl -Me  -Cl -Me

A58#  A58 #
-Br -Me  -Br -Me

A59#  A59 #
-I -Me  -I -Me

A60a#  A60a #
-2Py -Me  -2Py -Me

A60b#  A60b #
-3Py -Me  -3Py -Me

A60c#  A60c #
-4Py -Me  -4Py -Me

No  Do not
-R11 -R12  -R11 -R12

Al#  To the#
-H -H  -H H

A2#  A2 #
-Me -H  -Me -H

A3#  A3 #
-Et -H  -Et -H

A4#  A4 #
-nPr -H  -nPr -H

A5#  TO 5#
-iPr -H  -iPr -H

A6#  A6 #
-cPr -H  -cPr -H

Al#  To the#
-cBu -H  -cBu -H

AS#  ACE#
-0 -H  -0 -H

A9#  A9 #
-H    -H

A10#  A10 #
-G> -H  -G> -H

All#  All #
-cf3 -H  -cf3 -H

A12#  A12 #
-CN -H  -CN -H

A13#  A13 #
-Ph -H  -Ph -H

A14#  A14 #
-OMe -H  -OMe -H

A15#  A15 #
-OEt -H  -OEt -H

A16#  A16 #
-OnPr -H  -OnPr -H

A17#  A17 #
-OiPr -H  -OiPr -H

A18#  A18 #
-OcPr -H  -OcPr -H

A19#  A19 #
-OCH2cPr -H  -OCH2cPr -H

A20#  TO 20#
-ochcf2 -H  -ochcf2 -H

A21#  A21 #
-ocf3 -H  -ocf3 -H

All#  All #
-och2cf3 -H  -och2cf3 -H

A23#  A23 #
-och2ch2f -H  -och2ch2f -H

Aim  Aim
-OCH2CH2OMe -H  -OCH2CH2OMe -H

A15#  A15 #
-OCH2CH2NMe2 -H  -OCH2CH2NMe2 -H

A26#  A26 #
-F -H  -F -H

All#  All #
-Cl -H  -Cl -H

A28#  A28 #
-Br -H  -Br -H

A29#  A29 #
-I -H  -I -H

A30a#  A30a #
-2Py -H  -2Py -H

A3 Ob#  A3 Ob #
-3Py -H  -3Py -H

A30c#  A30c #
-4Py -H  -4Py -H

imagen143image143

No  Do not
-R11  -R11

B61#  B61 #
-H -cPr  -H -cPr

B62#  B62 #
-Me -cPr  -Me -cPr

B63#  B63 #
-Et -cPr  -Et -cPr

B64#  B64 #
-nPr -cPr  -nPr -cPr

B65#  B65 #
-iPr -cPr  -iPr -cPr

B66#  B66 #
-cPr -cPr  -cPr -cPr

B67#  B67 #
-cBu -cPr  -cBu -cPr

B68#  B68 #
-0 -cPr  -0 -cPr

B69#  B69 #
-cPr    -cPr

B70#  B70 #
-0> -cPr  -0> -cPr

B71#  B71 #
-cf3 -cPr  -cf3 -cPr

B72#  B72 #
-CN -cPr  -CN -cPr

B73#  B73 #
-Ph -cPr  -Ph -cPr

B74#  B74 #
-OMe -cPr  -OMe -cPr

B75#  B75 #
-OEt -cPr  -OEt -cPr

B76#  B76 #
-OnPr -cPr  -OnPr -cPr

B77#  B77 #
-OiPr -cPr  -OiPr -cPr

B78#  B78 #
-OcPr -cPr  -OcPr -cPr

B79#  B79 #
-OCH2cPr -cPr  -OCH2cPr -cPr

B80#  B80 #
-OCHCF2 -cPr  -OCHCF2 -cPr

B81#  B81 #
-OCF3 -cPr  -OCF3 -cPr

B82#  B82 #
-OCH2CF3 -cPr  -OCH2CF3 -cPr

B83#  B83 #
-OCH2CH2F -cPr  -OCH2CH2F -cPr

B84#  B84 #
-OCH2CH2OMe -cPr  -OCH2CH2OMe -cPr

B85#  B85 #
-OCH2CH2NMe2 -cPr  -OCH2CH2NMe2 -cPr

B86#  B86 #
-F -cPr  -F -cPr

B87#  B87 #
-Cl -cPr  -Cl -cPr

B88#  B88 #
-Br -cPr  -Br -cPr

B89#  B89 #
-I -cPr  -I -cPr

B90a#  B90a #
-2Py -cPr  -2Py -cPr

B90b#  B90b #
-3Py -cPr  -3Py -cPr

B90c#  B90c #
-4Py -cPr  -4Py -cPr

No  Do not
-R"  -R "

B31  B31
-H -iPr  -H -iPr

B32  B32
-Me -iPr  -Me -iPr

B33  B33
-Et -iPr  -Et -iPr

B34  B34
-nPr -iPr  -nPr -iPr

B35  B35
-iPr -iPr  -iPr -iPr

B36#  B36 #
-cPr -iPr  -cPr -iPr

B37#  B37 #
-cBu -iPr  -cBu -iPr

B38#  B38 #
-a -iPr  -a -iPr

B39#  B39 #
-iPr    -iPr

B40#  B40 #
0 -iPr  0 -iPr

B41  B41
-cf3 -iPr  -cf3 -iPr

B42#  B42 #
-CN -iPr  -CN -iPr

B43#  B43 #
-Ph -iPr  -Ph -iPr

B44  B44
-OMe -iPr  -OMe -iPr

B45  B45
-OEt -iPr  -OEt -iPr

B46  B46
-OnPr -iPr  -OnPr -iPr

B47  B47
-OiPr -iPr  -OiPr -iPr

B48#  B48 #
-OcPr -iPr  -OcPr -iPr

B49#  B49 #
-OCH2cPr -iPr  -OCH2cPr -iPr

B50  B50
-OCHCF2 -iPr  -OCHCF2 -iPr

B51  B51
-OCF3 -iPr  -OCF3 -iPr

B52  B52
-OCH2CF3 -iPr  -OCH2CF3 -iPr

B53  B53
-OCH2CH2F -iPr  -OCH2CH2F -iPr

B54#  B54 #
-OCH2CH2OMe -iPr  -OCH2CH2OMe -iPr

B55#  B55 #
-OCH2CH2NMe2 -iPr  -OCH2CH2NMe2 -iPr

B56  B56
-F -iPr  -F -iPr

B57  B57
-Cl -iPr  -Cl -iPr

B58  B58
-Br -iPr  -Br -iPr

B59  B59
-I -iPr  -I -iPr

B60a#  B60a #
-2Py -iPr  -2Py -iPr

B60b#  B60b #
-3Py -iPr  -3Py -iPr

B60c#  B60c #
-4Py -iPr  -4Py -iPr

No  Do not
-Ru  -Ru

Bl#  Bl #
-H -nPr  -H -nPr

B2#  B2 #
-Me -nPr  -Me -nPr

B3#  B3 #
-Et -nPr  -Et -nPr

B4#  B4 #
-nPr -nPr  -nPr -nPr

B5#  B5 #
-iPr -nPr  -iPr -nPr

B6#  B6 #
-cPr -nPr  -cPr -nPr

B7#  B7 #
-cBu -nPr  -cBu -nPr

B8#  B8 #
-nPr    -nPr

B9#  B9 #
-nPr    -nPr

BIO#  BIO #
-nPr    -nPr

Bll#  Bll #
-CF3 -nPr  -CF3 -nPr

B12#  B12 #
-CN -nPr  -CN -nPr

B13#  B13 #
-Ph -nPr  -Ph -nPr

B14#  B14 #
-OMe -nPr  -OMe -nPr

B15#  B15 #
-OEt -nPr  -OEt -nPr

B16#  B16 #
-OnPr -nPr  -OnPr -nPr

B17#  B17 #
-OiPr -nPr  -OiPr -nPr

B18#  B18 #
-OcPr -nPr  -OcPr -nPr

B19#  B19 #
-OCH2cPr -nPr  -OCH2cPr -nPr

B20#  B20 #
-OCHCF2 -nPr  -OCHCF2 -nPr

B21#  B21 #
-OCF3 -nPr  -OCF3 -nPr

B22#  B22 #
-OCH2CF3 -nPr  -OCH2CF3 -nPr

B23#  B23 #
-OCH2CH2F -nPr  -OCH2CH2F -nPr

B24#  B24 #
-OCH2CH2OMe -nPr  -OCH2CH2OMe -nPr

B25#  B25 #
-OCH2CH2NMe2 -nPr  -OCH2CH2NMe2 -nPr

B26#  B26 #
-F -nPr  -F -nPr

B27#  B27 #
-Cl -nPr  -Cl -nPr

B28#  B28 #
-Br -nPr  -Br -nPr

B29#  B29 #
-I -nPr  -I -nPr

B30a#  B30a #
-2Py -nPr  -2Py -nPr

B30b#  B30b #
-3Py -nPr  -3Py -nPr

B30c#  B30c #
-4Py -nPr  -4Py -nPr

imagen144image144

No  Do not
-Rn R12  -Rn R12

C61#  C61 #
-H -I  -H -I

C62#  C62 #
-Me -I  -Me -I

C63#  C63 #
-Et -I  -Et -I

C64#  C64 #
-nPr -I  -nPr -I

C65#  C65 #
-iPr -I  -iPr -I

C66#  C66 #
-cPr -I  -cPr -I

C67#  C67 #
-cBu -I  -cBu -I

C68#  C68 #
-0 -I  -0 -I

C69#  C69 #
-o -I  -or -I

C70#  C70 #
-o -I  -or -I

C71#  C71 #
-cf3 -I  -cf3 -I

C72#  C72 #
-CN -I  -CN -I

C73#  C73 #
-Ph -I  -Ph -I

C74#  C74 #
-OMe -I  -OMe -I

C75#  C75 #
-OEt -I  -OEt -I

C76#  C76 #
-OnPr -I  -OnPr -I

C77#  C77 #
-OiPr -I  -OiPr -I

C78#  C78 #
-OcPr -I  -OcPr -I

C79#  C79 #
-OCH2cPr -I  -OCH2cPr -I

C80#  C80 #
-OCHCF2 -I  -OCHCF2 -I

C81#  C81 #
-OCF3 -I  -OCF3 -I

C82#  C82 #
-OCH2CF3 -I  -OCH2CF3 -I

C83#  C83 #
-OCH2CH2F -I  -OCH2CH2F -I

C84#  C84 #
-OCH2CH2OMe -I  -OCH2CH2OMe -I

C85#  C85 #
-OCH2CH2NMe2 -I  -OCH2CH2NMe2 -I

C86#  C86 #
-F -I  -F -I

C87#  C87 #
-Cl -I  -Cl -I

C88#  C88 #
-Br -I  -Br -I

C89#  C89 #
-I -I  -I -I

C90a#  C90a #
-2Py -I  -2Py -I

C90b#  C90b #
-3Py -I  -3Py -I

C90c#  C90c #
-4Py -I  -4Py -I

No  Do not
-R11 R12  -R11 R12

C31#  C31 #
-H -Br  -H -Br

C32#  C32 #
-Me -Br  -Me -Br

C33#  C33 #
-Et -Br  -Et -Br

C34#  C34 #
-nPr -Br  -nPr -Br

C35#  C35 #
-iPr -Br  -iPr -Br

C36#  C36 #
-cPr -Br  -cPr -Br

C37#  C37 #
-cBu -Br  -cBu -Br

C38#  C38 #
-Br    -Br

C39#  C39 #
-Br    -Br

C40#  C40 #
-O’ -Br  -O ’-Br

C41#  C41 #
-cf3 -Br  -cf3 -Br

C42#  C42 #
-CN -Br  -CN -Br

C43#  C43 #
-Ph -Br  -Ph -Br

C44#  C44 #
-OMe -Br  -OMe -Br

C45#  C45 #
-OEt -Br  -OEt -Br

C46#  C46 #
-OnPr -Br  -OnPr -Br

C47#  C47 #
-OiPr -Br  -OiPr -Br

C48#  C48 #
-OcPr -Br  -OcPr -Br

C49#  C49 #
-OCH2cPr -Br  -OCH2cPr -Br

C50#  C50 #
-OCHCF2 -Br  -OCHCF2 -Br

C51#  C51 #
-OCF3 -Br  -OCF3 -Br

C52#  C52 #
-OCH2CF3 -Br  -OCH2CF3 -Br

C53#  C53 #
-OCH2CH2F -Br  -OCH2CH2F -Br

C54#  C54 #
-OCH2CH2OMe -Br  -OCH2CH2OMe -Br

C55#  C55 #
-OCH2CH2NMe2 -Br  -OCH2CH2NMe2 -Br

C56#  C56 #
-F -Br  -F -Br

C57#  C57 #
-Cl -Br  -Cl -Br

C58#  C58 #
-Br -Br  -Br -Br

C59#  C59 #
-I -Br  -I -Br

C60a#  C60a #
-2Py -Br  -2Py -Br

C60b#  C60b #
-3Py -Br  -3Py -Br

C60c#  C60c #
-4Py -Br  -4Py -Br

No  Do not
-R11 R12  -R11 R12

Cl  Cl
-H -Cl  -H -Cl

C2  C2
-Me -Cl  -Me -Cl

C3  C3
-Et -Cl  -Et -Cl

C4  C4
-nPr -Cl  -nPr -Cl

C5  C5
-iPr -Cl  -iPr -Cl

C6#  C6 #
-cPr -Cl  -cPr -Cl

Cl#  Cl #
-cBu -Cl  -cBu -Cl

C8#  C8 #
-0 -Cl  -0 -Cl

C9#  C9 #
-O -Cl  -O -Cl

CIO#  CIO #
-O’ -Cl  -O ’-Cl

Cll  Cll
-cf3 -Cl  -cf3 -Cl

C12#  C12 #
-CN -Cl  -CN -Cl

C13#  C13 #
-Ph -Cl  -Ph -Cl

C14  C14
-OMe -Cl  -OMe -Cl

C15  C15
-OEt -Cl  -OEt -Cl

C16  C16
-OnPr -Cl  -OnPr -Cl

C17  C17
-OiPr -Cl  -OiPr -Cl

C18#  C18 #
-OcPr -Cl  -OcPr -Cl

C19#  C19 #
-OCH2cPr -Cl  -OCH2cPr -Cl

C20  C20
-OCHCF2 -Cl  -OCHCF2 -Cl

C21  C21
-OCF3 -Cl  -OCF3 -Cl

C22  C22
-OCH2CF3 -Cl  -OCH2CF3 -Cl

C23  C23
-OCH2CH2F -Cl  -OCH2CH2F -Cl

C24#  C24 #
-OCH2CH2OMe -Cl  -OCH2CH2OMe -Cl

CIS#  CIS #
-OCH2CH2NMe2 -Cl  -OCH2CH2NMe2 -Cl

C26  C26
-F -Cl  -F -Cl

Cll  Cll
-Cl -Cl  -Cl -Cl

C28  C28
-Br -Cl  -Br -Cl

C29  C29
-I -Cl  -I -Cl

C30a#  C30a #
-2Py -Cl  -2Py -Cl

C30b#  C30b #
-3Py -Cl  -3Py -Cl

C30c#  C30c #
-4Py -Cl  -4Py -Cl

imagen145image145

H HH H

No  Do not
Ir11 -R u  Ir11 -R u

D61  D61
-H -Et  -H -Et

D62  D62
-Me -Et  -Me -Et

D63  D63
-Et -Et  -Et -Et

D64  D64
-nPr -Et  -nPr -Et

D65  D65
-iPr -Et  -iPr -Et

D66#  D66 #
-cPr -Et  -cPr -Et

D67#  D67 #
-cBu -Et  -cBu -Et

D68#  D68 #
-0 -Et  -0 -Et

D69#  D69 #
-o -Et  -o -Et

D70#  D70 #
-Et    -Et

D71  D71
-cf3 -Et  -cf3 -Et

D72#  D72 #
-CN -Et  -CN -Et

D73#  D73 #
-Ph -Et  -Ph -Et

D74  D74
-OMe -Et  -OMe -Et

D75  D75
-OEt -Et  -OEt -Et

D76  D76
-OnPr -Et  -OnPr -Et

D77  D77
-OiPr -Et  -OiPr -Et

D78#  D78 #
-OcPr -Et  -OcPr -Et

D79#  D79 #
-0CH2cPr -Et  -0CH2cPr -Et

D80  D80
-OCHCF2 -Et  -OCHCF2 -Et

D81  D81
-OCF3 -Et  -OCF3 -Et

D82  D82
-OCH2CF3 -Et  -OCH2CF3 -Et

D83  D83
-OCH2CH2F -Et  -OCH2CH2F -Et

D84#  D84 #
-OCH2CH2OMe -Et  -OCH2CH2OMe -Et

D85#  D85 #
-OCH2CH2NMe2 -Et  -OCH2CH2NMe2 -Et

D86  D86
-F -Et  -F -Et

D87  D87
-Cl -Et  -Cl -Et

D88  D88
-Br -Et  -Br -Et

D89  D89
-I -Et  -I -Et

D90a#  D90a #
-2Py -Et  -2Py -Et

D90b#  D90b #
-3Py -Et  -3Py -Et

D90c#  D90c #
-4Py -Et  -4Py -Et

No  Do not
-R"  -R "

D31#  D31 #
-H -Me  -H -Me

D32#  D32 #
-Me -Me  -Me -Me

D33#  D33 #
-Et -Me  -Et -Me

D34#  D34 #
-nPr -Me  -nPr -Me

D35#  D35 #
-iPr -Me  -iPr -Me

D36#  D36 #
-cPr -Me  -cPr -Me

D37#  D37 #
-cBu -Me  -cBu -Me

D38#  D38 #
-0 -Me  -0 -Me

D39#  D39 #
-Me    -I

D40#  D40 #
-O’ -Me  -O ’-Me

D41#  D41 #
-cf3 -Me  -cf3 -Me

D42#  D42 #
-CN -Me  -CN -Me

D43#  D43 #
-Ph -Me  -Ph -Me

D44#  D44 #
-OMe -Me  -OMe -Me

D45#  D45 #
-OEt -Me  -OEt -Me

D46#  D46 #
-OnPr -Me  -OnPr -Me

D47#  D47 #
-OiPr -Me  -OiPr -Me

D48#  D48 #
-OcPr -Me  -OcPr -Me

D49#  D49 #
-OCH2cPr -Me  -OCH2cPr -Me

D50#  D50 #
-OCHCF2 -Me  -OCHCF2 -Me

D51#  D51 #
-OCF3 -Me  -OCF3 -Me

D52#  D52 #
-OCH2CF3 -Me  -OCH2CF3 -Me

D53#  D53 #
-OCH2CH2F -Me  -OCH2CH2F -Me

D54#  D54 #
-OCH2CH2OMe -Me  -OCH2CH2OMe -Me

D55#  D55 #
-OCH2CH2NMe2 -Me  -OCH2CH2NMe2 -Me

D56#  D56 #
-F -Me  -F -Me

D57#  D57 #
-Cl -Me  -Cl -Me

D58#  D58 #
-Br -Me  -Br -Me

D59#  D59 #
-I -Me  -I -Me

D60a#  D60a #
-2Py -Me  -2Py -Me

D60b#  D60b #
-3Py -Me  -3Py -Me

D60c#  D60c #
-4Py -Me  -4Py -Me

No  Do not
-R" XT  -R "XT

Dl#  Dl #
-H -H  -H H

D2#  D2 #
-Me -H  -Me -H

D3#  D3 #
-Et -H  -Et -H

D4#  D4 #
-nPr -H  -nPr -H

D5#  D5 #
-iPr -H  -iPr -H

D6#  D6 #
-cPr -H  -cPr -H

D7#  D7 #
-cBu -H  -cBu -H

D8#  D8 #
-0 -H  -0 -H

D9#  D9 #
-O -H  -OR -H

DIO#  IT GAVE#
-H    -H

Dll#  Dll #
-cf3 -H  -cf3 -H

D12#  D12 #
-CN -H  -CN -H

D13#  D13 #
-Ph -H  -Ph -H

D14#  D14 #
-OMe -H  -OMe -H

D15#  D15 #
-OEt -H  -OEt -H

D16#  D16 #
-OnPr -H  -OnPr -H

D17#  D17 #
-OiPr -H  -OiPr -H

D18#  D18 #
-OcPr -H  -OcPr -H

D19#  D19 #
-OCH2cPr -H  -OCH2cPr -H

D20#  D20 #
-OCHCF2 -H  -OCHCF2 -H

D21#  D21 #
-OCF3 -H  -OCF3 -H

D22#  D22 #
-OCH2CF3 -H  -OCH2CF3 -H

D23#  D23 #
-OCH2CH2F -H  -OCH2CH2F -H

D24#  D24 #
-OCH2CH2OMe -H  -OCH2CH2OMe -H

D25#  D25 #
-OCH2CH2NMe2 -H  -OCH2CH2NMe2 -H

D26#  D26 #
-F -H  -F -H

D27#  D27 #
-Cl -H  -Cl -H

D28#  D28 #
-Br -H  -Br -H

D29#  D29 #
-I -H  -I -H

D30a#  D30a #
-2Py -H  -2Py -H

D30b#  D30b #
-3Py -H  -3Py -H

D30c#  D30c #
-4Py -H  -4Py -H

imagen146image146

No  Do not
-R“ -R12  -R “-R12

E61#  E61 #
-H -cPr  -H -cPr

E62#  E62 #
-Me -cPr  -Me -cPr

E63#  E63 #
-Et -cPr  -Et -cPr

E64#  E64 #
-nPr -cPr  -nPr -cPr

E65#  E65 #
-iPr -cPr  -iPr -cPr

E66#  E66 #
-cPr -cPr  -cPr -cPr

E67#  E67 #
-cBu -cPr  -cBu -cPr

E68#  E68 #
-o -cPr  -o -cPr

E69#  E69 #
-cPr    -cPr

E70#  E70 #
-C° -cPr  -C ° -cPr

E71#  E71 #
-cf3 -cPr  -cf3 -cPr

E72#  E72 #
-CN -cPr  -CN -cPr

E73#  E73 #
-Ph -cPr  -Ph -cPr

E74#  E74 #
-OMe -cPr  -OMe -cPr

E75#  E75 #
-OEt -cPr  -OEt -cPr

E76#  E76 #
-OnPr -cPr  -OnPr -cPr

E77#  E77 #
-OiPr -cPr  -OiPr -cPr

E78#  E78 #
-OcPr -cPr  -OcPr -cPr

E79#  E79 #
-OCH2cPr -cPr  -OCH2cPr -cPr

E80#  E80 #
-OCHCF2 -cPr  -OCHCF2 -cPr

E81#  E81 #
-OCF3 -cPr  -OCF3 -cPr

E82#  E82 #
-OCH2CF3 -cPr  -OCH2CF3 -cPr

E83#  E83 #
-OCH2CH2F -cPr  -OCH2CH2F -cPr

E84#  E84 #
-OCH2CH2OMe -cPr  -OCH2CH2OMe -cPr

E85#  E85 #
-OCH2CH2NMe2 -cPr  -OCH2CH2NMe2 -cPr

E86#  E86 #
-F -cPr  -F -cPr

E87#  E87 #
-Cl -cPr  -Cl -cPr

E88#  E88 #
-Br -cPr  -Br -cPr

E89#  E89 #
-I -cPr  -I -cPr

E90a#  E90a #
-2Py -cPr  -2Py -cPr

E90b#  E90b #
-3Py -cPr  -3Py -cPr

E90c#  E90c #
-4Py -cPr  -4Py -cPr

No  Do not
-Ru -Ru  -Ru -Ru

E31  E31
-H -iPr  -H -iPr

E32  E32
-Me -iPr  -Me -iPr

E33  E33
-Et -iPr  -Et -iPr

E34  E34
-nPr -iPr  -nPr -iPr

E35  E35
-iPr -iPr  -iPr -iPr

E36#  E36 #
-cPr -iPr  -cPr -iPr

E37#  E37 #
-cBu -iPr  -cBu -iPr

E38#  E38 #
-0 -iPr  -0 -iPr

E39#  E39 #
-iPr    -iPr

E40#  E40 #
-O -iPr  -OR -iPr

E41  E41
-cf3 -iPr  -cf3 -iPr

E42#  E42 #
-CN -iPr  -CN -iPr

E43#  E43 #
-Ph -iPr  -Ph -iPr

E44  E44
-OMe -iPr  -OMe -iPr

E45  E45
-OEt -iPr  -OEt -iPr

E46  E46
-OnPr -iPr  -OnPr -iPr

E47  E47
-OiPr -iPr  -OiPr -iPr

E48#  E48 #
-OcPr -iPr  -OcPr -iPr

E49#  E49 #
-OCH2cPr -iPr  -OCH2cPr -iPr

E50  E50
-OCHCF2 -iPr  -OCHCF2 -iPr

E51  E51
-OCF3 -iPr  -OCF3 -iPr

E52  E52
-OCH2CF3 -iPr  -OCH2CF3 -iPr

E53  E53
-OCH2CH2F -iPr  -OCH2CH2F -iPr

E54#  E54 #
-OCH2CH2OMe -iPr  -OCH2CH2OMe -iPr

E55#  E55 #
-OCH2CH2NMe2 -iPr  -OCH2CH2NMe2 -iPr

E56  E56
-F -iPr  -F -iPr

E57  E57
-Cl -iPr  -Cl -iPr

E58  E58
-Br -iPr  -Br -iPr

E59  E59
-I -iPr  -I -iPr

E60a#  E60a #
-2Py -iPr  -2Py -iPr

E60b#  E60b #
-3Py -iPr  -3Py -iPr

E60c#  E60c #
-4Py -iPr  -4Py -iPr

No  Do not
-R“  -R "

El#  He#
-H -nPr  -H -nPr

E2#  E2 #
-Me -nPr  -Me -nPr

E3#  E3 #
-Et -nPr  -Et -nPr

E4#  E4 #
-nPr -nPr  -nPr -nPr

E5#  E5 #
-iPr -nPr  -iPr -nPr

E6#  E6 #
-cPr -nPr  -cPr -nPr

E7#  E7 #
-cBu -nPr  -cBu -nPr

E8#  E8 #
-0 -nPr  -0 -nPr

E9#  E9 #
-nPr    -nPr

E10#  E10 #
-O -nPr  -O -nPr

Ell#  Ell #
-CF3 -nPr  -CF3 -nPr

E12#  E12 #
-CN -nPr  -CN -nPr

E13#  E13 #
-Ph -nPr  -Ph -nPr

E14#  E14 #
-OMe -nPr  -OMe -nPr

E15#  E15 #
-OEt -nPr  -OEt -nPr

E16#  E16 #
-OnPr -nPr  -OnPr -nPr

E17#  E17 #
-OiPr -nPr  -OiPr -nPr

E18#  E18 #
-OcPr -nPr  -OcPr -nPr

El 9#  The 9#
-OCH2cPr -nPr  -OCH2cPr -nPr

E20#  E20 #
-OCHCF2 -nPr  -OCHCF2 -nPr

E21#  E21 #
-OCF3 -nPr  -OCF3 -nPr

E22#  E22 #
-OCH2CF3 -nPr  -OCH2CF3 -nPr

E23#  E23 #
-OCH2CH2F -nPr  -OCH2CH2F -nPr

E24#  E24 #
-OCH2CH2OMe -nPr  -OCH2CH2OMe -nPr

E25#  E25 #
-OCH2CH2NMe2 -nPr  -OCH2CH2NMe2 -nPr

E26#  E26 #
-F -nPr  -F -nPr

E27#  E27 #
-Cl -nPr  -Cl -nPr

E28#  E28 #
-Br -nPr  -Br -nPr

E29#  E29 #
-I -nPr  -I -nPr

E30a#  E30a #
-2Py -nPr  -2Py -nPr

E30b#  E30b #
-3Py -nPr  -3Py -nPr

E30c#  E30c #
-4Py -nPr  -4Py -nPr

imagen147image147

H HH H

No  Do not
-R11 R12  -R11 R12

F61#  F61 #
-H -I  -H -I

F62#  F62 #
-Me -I  -Me -I

F63#  F63 #
-Et -I  -Et -I

F64#  F64 #
-nPr -I  -nPr -I

F65#  F65 #
-iPr -I  -iPr -I

F66#  F66 #
-cPr -I  -cPr -I

F67#  F67 #
-cBu -I  -cBu -I

F68#  F68 #
-I    -I

F69#  F69 #
-I    -I

F70#  F70 #
-G» -I  -G »-I

F71#  F71 #
-cf3 -I  -cf3 -I

F72#  F72 #
-CN -I  -CN -I

F73#  F73 #
-Ph -I  -Ph -I

F74#  F74 #
-OMe -I  -OMe -I

F75#  F75 #
-OEt -I  -OEt -I

F76#  F76 #
-OnPr -I  -OnPr -I

F77#  F77 #
-OiPr -I  -OiPr -I

F78#  F78 #
-OcPr -I  -OcPr -I

F79#  F79 #
-OCH2cPr -I  -OCH2cPr -I

F80#  F80 #
-OCHCF2 -I  -OCHCF2 -I

F81#  F81 #
-OCF3 -I  -OCF3 -I

F82#  F82 #
-OCH2CF3 -I  -OCH2CF3 -I

F83#  F83 #
-och2ch2f -I  -och2ch2f -I

F84#  F84 #
-OCH2CH2OMe -I  -OCH2CH2OMe -I

F85#  F85 #
-OCH2CH2NMe2 -I  -OCH2CH2NMe2 -I

F86#  F86 #
-F -I  -F -I

F87#  F87 #
-Cl -I  -Cl -I

F88#  F88 #
-Br -I  -Br -I

F89#  F89 #
-I -I  -I -I

F90a#  F90a #
-2Py -I  -2Py -I

F90b#  F90b #
-3Py -I  -3Py -I

F90c#  F90c #
-4Py -I  -4Py -I

No  Do not
-R11 R12  -R11 R12

F31#  F31 #
-H -Br  -H -Br

F32#  F32 #
-Me -Br  -Me -Br

F33#  F33 #
-Et -Br  -Et -Br

F34#  F34 #
-nPr -Br  -nPr -Br

F35#  F35 #
-iPr -Br  -iPr -Br

F36#  F36 #
-cPr -Br  -cPr -Br

F37#  F37 #
-cBu -Br  -cBu -Br

F38#  F38 #
-Br    -Br

F39#  F39 #
^3 -Br  ^ 3 -Br

F40#  F40 #
-O -Br  -OR -Br

F41#  F41 #
-cf3 -Br  -cf3 -Br

F42#  F42 #
-CN -Br  -CN -Br

F43#  F43 #
-Ph -Br  -Ph -Br

F44#  F44 #
-OMe -Br  -OMe -Br

F45#  F45 #
-OEt -Br  -OEt -Br

F46#  F46 #
-OnPr -Br  -OnPr -Br

F47#  F47 #
-OiPr -Br  -OiPr -Br

F48#  F48 #
-OcPr -Br  -OcPr -Br

F49#  F49 #
-OCH2cPr -Br  -OCH2cPr -Br

F50#  F50 #
-ochcf2 -Br  -ochcf2 -Br

F51#  F51 #
-ocf3 -Br  -ocf3 -Br

F52#  F52 #
-och2cf3 -Br  -och2cf3 -Br

F53#  F53 #
-och2ch2f -Br  -och2ch2f -Br

F54#  F54 #
-OCH2CH2OMe -Br  -OCH2CH2OMe -Br

F55#  F55 #
-OCH2CH2NMe2 -Br  -OCH2CH2NMe2 -Br

F56#  F56 #
-F -Br  -F -Br

F57#  F57 #
-Cl -Br  -Cl -Br

F58#  F58 #
-Br -Br  -Br -Br

F59#  F59 #
-I -Br  -I -Br

F60a#  F60a #
-2Py -Br  -2Py -Br

F60b#  F60b #
-3Py -Br  -3Py -Br

F60c#  F60c #
-4Py -Br  -4Py -Br

No  Do not
-Rn R12  -Rn R12

FI  FI
-H -Cl  -H -Cl

F2  F2
-Me -Cl  -Me -Cl

F3  F3
-Et -Cl  -Et -Cl

F4  F4
-nPr -Cl  -nPr -Cl

F5  F5
-iPr -Cl  -iPr -Cl

F6#  F6 #
-cPr -Cl  -cPr -Cl

F7#  F7 #
-cBu -Cl  -cBu -Cl

F8#  F8 #
-Cl    -Cl

F9#  F9 #
-O -Cl  -O -Cl

F10#  F10 #
-Cl    -Cl

FI 1  FI 1
-cf3 -Cl  -cf3 -Cl

F12#  F12 #
-CN -Cl  -CN -Cl

F13#  F13 #
-Ph -Cl  -Ph -Cl

F14  F14
-OMe -Cl  -OMe -Cl

F15  F15
-OEt -Cl  -OEt -Cl

F16  F16
-OnPr -Cl  -OnPr -Cl

F17  F17
-OiPr -Cl  -OiPr -Cl

F18#  F18 #
-OcPr -Cl  -OcPr -Cl

F19#  F19 #
-OCH2cPr -Cl  -OCH2cPr -Cl

F20  F20
-OCHCF2 -Cl  -OCHCF2 -Cl

F21  F21
-ocf3 -Cl  -ocf3 -Cl

F22  F22
-och2cf3 -Cl  -och2cf3 -Cl

F23  F23
-och2ch2f -Cl  -och2ch2f -Cl

F24#  F24 #
-OCH2CH2OMe -Cl  -OCH2CH2OMe -Cl

F25#  F25 #
-OCH2CH2NMe2 -Cl  -OCH2CH2NMe2 -Cl

F26  F26
-F -Cl  -F -Cl

F27  F27
-Cl -Cl  -Cl -Cl

F28  F28
-Br -Cl  -Br -Cl

F29  F29
-I -Cl  -I -Cl

F30a#  F30a #
-2Py -Cl  -2Py -Cl

F30b#  F30b #
-3Py -Cl  -3Py -Cl

F30c#  F30c #
-4Py -Cl  -4Py -Cl

imagen148image148

No  Do not
=R" -Ru  = R "-Ru

G61  G61
-H -Et  -H -Et

G62  G62
-Me -Et  -Me -Et

G63  G63
-Et -Et  -Et -Et

G64  G64
-nPr -Et  -nPr -Et

G65  G65
-iPr -Et  -iPr -Et

G66#  G66 #
-cPr -Et  -cPr -Et

G67#  G67 #
-cBu -Et  -cBu -Et

G68#  G68 #
-Et    -Et

G69#  G69 #
-Et    -Et

G70#  G70 #
-Q -Et  -Q -Et

G71  G71
-CF3 -Et  -CF3 -Et

G72#  G72 #
-CN -Et  -CN -Et

G73#  G73 #
-Ph -Et  -Ph -Et

G74  G74
-OMe -Et  -OMe -Et

G75  G75
-OEt -Et  -OEt -Et

G76  G76
-OnPr -Et  -OnPr -Et

G77  G77
-OiPr -Et  -OiPr -Et

G78#  G78 #
-OcPr -Et  -OcPr -Et

G79#  G79 #
-OCH2cPr -Et  -OCH2cPr -Et

G80  G80
-OCHCF2 -Et  -OCHCF2 -Et

G81  G81
-OCF3 -Et  -OCF3 -Et

G82  G82
-OCH2CF3 -Et  -OCH2CF3 -Et

G83  G83
-OCH2CH2F -Et  -OCH2CH2F -Et

G84#  G84 #
-OCH2CH2OMe -Et  -OCH2CH2OMe -Et

G85#  G85 #
-OCH2CH2NMe2 -Et  -OCH2CH2NMe2 -Et

G86  G86
-F -Et  -F -Et

G87  G87
-Cl -Et  -Cl -Et

G88  G88
-Br -Et  -Br -Et

G89  G89
-I -Et  -I -Et

G90a#  G90a #
-2Py -Et  -2Py -Et

G90b#  G90b #
-3Py -Et  -3Py -Et

G90c#  G90c #
-4Py -Et  -4Py -Et

No  Do not
-Ru -Ru  -Ru -Ru

Gl#  Gl #
-H -H  -H H

G2#  G2 #
-Me -H  -Me -H

G3#  G3 #
-Et -H  -Et -H

G4#  G4 #
-nPr -H  -nPr -H

G5#  G5 #
-iPr -H  -iPr -H

G6#  G6 #
-cPr -H  -cPr -H

G7#  G7 #
-cBu -H  -cBu -H

G8#  G8 #
-0 -H  -0 -H

G9#  G9 #
-O -H  -OR -H

G10#  G10 #
-O’ -H  -O ’-H

Gil#  Gil #
-CF3 -H  -CF3 -H

G12#  G12 #
-CN -H  -CN -H

G13#  G13 #
-Ph -H  -Ph -H

G14#  G14 #
-OMe -H  -OMe -H

G15#  G15 #
-OEt -H  -OEt -H

G16#  G16 #
-OnPr -H  -OnPr -H

G17#  G17 #
-OiPr -H  -OiPr -H

G18#  G18 #
-OcPr -H  -OcPr -H

G19#  G19 #
-OCH2cPr -H  -OCH2cPr -H

G20#  G20 #
-OCHCF2 -H  -OCHCF2 -H

G21#  G21 #
-OCF3 -H  -OCF3 -H

G22#  G22 #
-OCH2CF3 -H  -OCH2CF3 -H

G23#  G23 #
-OCH2CH2F -H  -OCH2CH2F -H

G24#  G24 #
-OCH2CH2OMe -H  -OCH2CH2OMe -H

G25#  G25 #
-OCH2CH2NMe2 -H  -OCH2CH2NMe2 -H

G26#  G26 #
-F -H  -F -H

G27#  G27 #
-Cl -H  -Cl -H

G28#  G28 #
-Br -H  -Br -H

G29#  G29 #
-I -H  -I -H

G30a#  G30a #
-2Py -H  -2Py -H

G30b#  G30b #
-3Py -H  -3Py -H

G30c#  G30c #
-4Py -H  -4Py -H

No  Do not
-R“  -R "

G31#  G31 #
-H -Me  -H -Me

G32#  G32 #
-Me -Me  -Me -Me

G33#  G33 #
-Et -Me  -Et -Me

G34#  G34 #
-nPr -Me  -nPr -Me

G35#  G35 #
-iPr -Me  -iPr -Me

G36#  G36 #
-cPr -Me  -cPr -Me

G37#  G37 #
-cBu -Me  -cBu -Me

G38#  G38 #
-0 -Me  -0 -Me

G39#  G39 #
-Me    -I

G40#  G40 #
-Q -Me  -Q -Me

G41#  G41 #
-CF3 -Me  -CF3 -Me

G42#  G42 #
-CN -Me  -CN -Me

G43#  G43 #
-Ph -Me  -Ph -Me

G44#  G44 #
-OMe -Me  -OMe -Me

G45#  G45 #
-OEt -Me  -OEt -Me

G46#  G46 #
-OnPr -Me  -OnPr -Me

G47#  G47 #
-OiPr -Me  -OiPr -Me

G48#  G48 #
-OcPr -Me  -OcPr -Me

G49#  G49 #
-OCH2cPr -Me  -OCH2cPr -Me

G50#  G50 #
-OCHCF2 -Me  -OCHCF2 -Me

G51#  G51 #
-OCF3 -Me  -OCF3 -Me

G52#  G52 #
-OCH2CF3 -Me  -OCH2CF3 -Me

G53#  G53 #
-OCH2CH2F -Me  -OCH2CH2F -Me

G54#  G54 #
-OCH2CH2OMe -Me  -OCH2CH2OMe -Me

G55#  G55 #
-OCH2CH2NMe2 -Me  -OCH2CH2NMe2 -Me

G56#  G56 #
-F -Me  -F -Me

G57#  G57 #
-Cl -Me  -Cl -Me

G58#  G58 #
-Br -Me  -Br -Me

G59#  G59 #
-I -Me  -I -Me

G60a#  G60a #
-2Py -Me  -2Py -Me

G60b#  G60b #
-3Py -Me  -3Py -Me

G60c#  G60c #
-4Py -Me  -4Py -Me

imagen149image149

imagen150image150

No  Do not
-R11  -R11

161#  161 #
-H -I  -H -I

162#  162 #
-Me -I  -Me -I

163#  163 #
-Et -I  -Et -I

164#  164 #
-nPr -I  -nPr -I

165#  165 #
-iPr -I  -iPr -I

166#  166 #
-cPr -I  -cPr -I

167#  167 #
-cBu -I  -cBu -I

168#  168 #
-I    -I

169#  169 #
-O -I  -OR -I

170#  170 #
-I    -I

171#  171 #
-cf3 -I  -cf3 -I

172#  172 #
-CN -I  -CN -I

173#  173 #
-Ph -I  -Ph -I

174#  174 #
-OMe -I  -OMe -I

175#  175 #
-OEt -I  -OEt -I

176#  176 #
-OnPr -I  -OnPr -I

177#  177 #
-OiPr -I  -OiPr -I

178#  178 #
-OcPr -I  -OcPr -I

179#  179 #
-OCH2cPr -I  -OCH2cPr -I

180#  180 #
-OCHCF2 -I  -OCHCF2 -I

181#  181 #
-OCF3 -I  -OCF3 -I

182#  182 #
-OCH2CF3 -I  -OCH2CF3 -I

183#  183 #
-OCH2CH2F -I  -OCH2CH2F -I

184#  184 #
-OCH2CH2OMe -I  -OCH2CH2OMe -I

185#  185 #
-OCH2CH2NMe2 -I  -OCH2CH2NMe2 -I

186#  186 #
-F -I  -F -I

187#  187 #
-Cl -I  -Cl -I

188#  188 #
-Br -I  -Br -I

189#  189 #
-I -I  -I -I

I90a#  I90a #
-2Py -I  -2Py -I

I90b#  I90b #
-3Py -I  -3Py -I

I90c#  I90c #
-4Py -I  -4Py -I

No  Do not
-R“ -R12  -R “-R12

131#  131 #
-H -Br  -H -Br

132#  132 #
-Me -Br  -Me -Br

133#  133 #
-Et -Br  -Et -Br

134#  134 #
-nPr -Br  -nPr -Br

135#  135 #
-iPr -Br  -iPr -Br

136#  136 #
-cPr -Br  -cPr -Br

137#  137 #
-cBu -Br  -cBu -Br

138#  138 #
-Br    -Br

139#  139 #
-Br    -Br

140#  140 #
O -Br  Or -Br

141#  141 #
-cf3 -Br  -cf3 -Br

142#  142 #
-CN -Br  -CN -Br

143#  143 #
-Ph -Br  -Ph -Br

144#  144 #
-OMe -Br  -OMe -Br

145#  145 #
-OEt -Br  -OEt -Br

146#  146 #
-OnPr -Br  -OnPr -Br

147#  147 #
-OiPr -Br  -OiPr -Br

148#  148 #
-OcPr -Br  -OcPr -Br

149#  149 #
-OCH2cPr -Br  -OCH2cPr -Br

150#  150 #
-OCHCF2 -Br  -OCHCF2 -Br

151#  151 #
-OCF3 -Br  -OCF3 -Br

152#  152 #
-OCH2CF3 -Br  -OCH2CF3 -Br

153#  153 #
-OCH2CH2F -Br  -OCH2CH2F -Br

154#  154 #
-OCH2CH2OMe -Br  -OCH2CH2OMe -Br

155#  155 #
-OCH2CH2NMe2 -Br  -OCH2CH2NMe2 -Br

156#  156 #
-F -Br  -F -Br

157#  157 #
-Cl -Br  -Cl -Br

158#  158 #
-Br -Br  -Br -Br

159#  159 #
-I -Br  -I -Br

I60a#  I60a #
-2Py -Br  -2Py -Br

I60b#  I60b #
-3Py -Br  -3Py -Br

I60c#  I60c #
-4Py -Br  -4Py -Br

No  Do not
-R“  -R "

11  eleven
-H -Cl  -H -Cl

12  12
-Me -Cl  -Me -Cl

13  13
-Et -Cl  -Et -Cl

14  14
-nPr -Cl  -nPr -Cl

15  fifteen
-iPr -Cl  -iPr -Cl

16#  16 #
-cPr -Cl  -cPr -Cl

17#  17 #
-cBu -Cl  -cBu -Cl

18#  18 #
-Cl    -Cl

19#  19 #
-Cl    -Cl

110#  110 #
-G> -Cl  -G> -Cl

111  111
-cf3 -Cl  -cf3 -Cl

112#  112 #
-CN -Cl  -CN -Cl

113#  113 #
-Ph -Cl  -Ph -Cl

114  114
-OMe -Cl  -OMe -Cl

115  115
-OEt -Cl  -OEt -Cl

116  116
-OnPr -Cl  -OnPr -Cl

117  117
-OiPr -Cl  -OiPr -Cl

118#  118 #
-OcPr -Cl  -OcPr -Cl

119#  119 #
-OCH2cPr -Cl  -OCH2cPr -Cl

120  120
-OCHCF2 -Cl  -OCHCF2 -Cl

121  121
-OCF3 -Cl  -OCF3 -Cl

122  122
-OCH2CF3 -Cl  -OCH2CF3 -Cl

123  123
-OCH2CH2F -Cl  -OCH2CH2F -Cl

124#  124 #
-OCH2CH2OMe -Cl  -OCH2CH2OMe -Cl

125#  125 #
-OCH2CH2NMe2 -Cl  -OCH2CH2NMe2 -Cl

126  126
-F -Cl  -F -Cl

127  127
-Cl -Cl  -Cl -Cl

128  128
-Br -Cl  -Br -Cl

129  129
-I -Cl  -I -Cl

I30a#  I30a #
-2Py -Cl  -2Py -Cl

13 0b#  13 0b #
-3Py -Cl  -3Py -Cl

13 0c#  13 0c #
-4Py -Cl  -4Py -Cl

imagen151image151

No  Do not
-R" -R12  -R "-R12

J31#  J31 #
-H -Me  -H -Me

J32#  J32 #
-Me -Me  -Me -Me

J33#  J33 #
-Et -Me  -Et -Me

J34#  J34 #
-nPr -Me  -nPr -Me

J35#  J35 #
-iPr -Me  -iPr -Me

J36#  J36 #
-cPr -Me  -cPr -Me

J37#  J37 #
-cBu -Me  -cBu -Me

J38#  J38 #
-0 -Me  -0 -Me

J39#  J39 #
-o -Me  -or -Me

J40#  J40 #
~0> -Me  ~ 0> -Me

J41#  J41 #
-cf3 -Me  -cf3 -Me

J42#  J42 #
-CN -Me  -CN -Me

J43#  J43 #
-Ph -Me  -Ph -Me

J44#  J44 #
-OMe -Me  -OMe -Me

J45#  J45 #
-OEt -Me  -OEt -Me

J46#  J46 #
-OnPr -Me  -OnPr -Me

J47#  J47 #
-OiPr -Me  -OiPr -Me

J48#  J48 #
-OcPr -Me  -OcPr -Me

J49#  J49 #
-OCH2cPr -Me  -OCH2cPr -Me

J50#  J50 #
-OCHCF2 -Me  -OCHCF2 -Me

J51#  J51 #
-OCF3 -Me  -OCF3 -Me

J52#  J52 #
-OCH2CF3 -Me  -OCH2CF3 -Me

J53#  J53 #
-OCH2CH2F -Me  -OCH2CH2F -Me

J54#  J54 #
-OCH2CH2OMe -Me  -OCH2CH2OMe -Me

J55#  J55 #
-OCH2CH2NMe2 -Me  -OCH2CH2NMe2 -Me

J56#  J56 #
-F -Me  -F -Me

J57#  J57 #
-Cl -Me  -Cl -Me

J58#  J58 #
-Br -Me  -Br -Me

J59#  J59 #
-I -Me  -I -Me

J60a#  J60a #
-2Py -Me  -2Py -Me

J60b#  J60b #
-3Py -Me  -3Py -Me

J60c#  J60c #
-4Py -Me  -4Py -Me

No  Do not
-R11 -R 2  -R11 -R 2

J61  J61
-H -Et  -H -Et

J62  J62
-Me -Et  -Me -Et

J63  J63
-Et -Et  -Et -Et

J64  J64
-nPr -Et  -nPr -Et

J65  J65
-iPr -Et  -iPr -Et

J66#  J66 #
-cPr -Et  -cPr -Et

J67#  J67 #
-cBu -Et  -cBu -Et

J68#  J68 #
-Et    -Et

J69#  J69 #
-Et    -Et

J70#  J70 #
-Et    -Et

J71  J71
-cf3 -Et  -cf3 -Et

J72#  J72 #
-CN -Et  -CN -Et

J73#  J73 #
-Ph -Et  -Ph -Et

J74  J74
-OMe -Et  -OMe -Et

J75  J75
-OEt -Et  -OEt -Et

J76  J76
-OnPr -Et  -OnPr -Et

J77  J77
-OiPr -Et  -OiPr -Et

J78#  J78 #
-OcPr -Et  -OcPr -Et

J79#  J79 #
-OCH2cPr -Et  -OCH2cPr -Et

J80  J80
-OCHCF2 -Et  -OCHCF2 -Et

J81  J81
-OCF3 -Et  -OCF3 -Et

J82  J82
-OCH2CF3 -Et  -OCH2CF3 -Et

J83  J83
-OCH2CH2F -Et  -OCH2CH2F -Et

J84#  J84 #
-OCH2CH2OMe -Et  -OCH2CH2OMe -Et

J85#  J85 #
-OCH2CH2NMe2 -Et  -OCH2CH2NMe2 -Et

J86  J86
-F -Et  -F -Et

J87  J87
-Cl -Et  -Cl -Et

J88  J88
-Br -Et  -Br -Et

J89  J89
-I -Et  -I -Et

J90a#  J90a #
-2Py -Et  -2Py -Et

J90b#  J90b #
-3Py -Et  -3Py -Et

J90c#  J90c #
-4Py -Et  -4Py -Et

No  Do not
-R" -R 2  -R "-R 2

Jl#  Jl #
-H -H  -H H

J2#  J2 #
-Me -H  -Me -H

J3#  J3 #
-Et -H  -Et -H

J4#  J4 #
-nPr -H  -nPr -H

J5#  J5 #
-iPr -H  -iPr -H

J6#  J6 #
-cPr -H  -cPr -H

J7#  J7 #
-cBu -H  -cBu -H

J8#  J8 #
-H    -H

J9#  J9 #
-H    -H

J10#  J10 #
-O -H  -OR -H

Jl 1#  Jl 1 #
-cf3 -H  -cf3 -H

J12#  J12 #
-CN -H  -CN -H

J13#  J13 #
-Ph -H  -Ph -H

J14#  J14 #
-OMe -H  -OMe -H

J15#  J15 #
-OEt -H  -OEt -H

J16#  J16 #
-OnPr -H  -OnPr -H

J17#  J17 #
-OiPr -H  -OiPr -H

J18#  J18 #
-OcPr -H  -OcPr -H

J19#  J19 #
-OCH2cPr -H  -OCH2cPr -H

J20#  J20 #
-ochcf2 -H  -ochcf2 -H

J21#  J21 #
-OCF3 -H  -OCF3 -H

J22#  J22 #
-OCH2CF3 -H  -OCH2CF3 -H

J23#  J23 #
-och2ch2f -H  -och2ch2f -H

J24#  J24 #
-OCH2CH2OMe -H  -OCH2CH2OMe -H

J25#  J25 #
-OCH2CH2NMe2 -H  -OCH2CH2NMe2 -H

J26#  J26 #
-F -H  -F -H

J27#  J27 #
-Cl -H  -Cl -H

J28#  J28 #
-Br -H  -Br -H

J29#  J29 #
-I -H  -I -H

J30a#  J30a #
-2Py -H  -2Py -H

J30b#  J30b #
-3Py -H  -3Py -H

J30c#  J30c #
-4Py -H  -4Py -H

imagen152image152

No  Do not
-R11 -R12  -R11 -R12

K61#  K61 #
-H -cPr  -H -cPr

K62#  K62 #
-Me -cPr  -Me -cPr

K63#  K63 #
-Et -cPr  -Et -cPr

K64#  K64 #
-nPr -cPr  -nPr -cPr

K65#  K65 #
-iPr -cPr  -iPr -cPr

K66#  K66 #
-cPr -cPr  -cPr -cPr

K67#  K67 #
-cBu -cPr  -cBu -cPr

K68#  K68 #
-0 -cPr  -0 -cPr

K69#  K69 #
-cPr    -cPr

K70#  K70 #
-cPr    -cPr

K71#  K71 #
-cf3 -cPr  -cf3 -cPr

K72#  K72 #
-CN -cPr  -CN -cPr

K73#  K73 #
-Ph -cPr  -Ph -cPr

K74#  K74 #
-OMe -cPr  -OMe -cPr

K75#  K75 #
-OEt -cPr  -OEt -cPr

K76#  K76 #
-OnPr -cPr  -OnPr -cPr

K77#  K77 #
-OiPr -cPr  -OiPr -cPr

K78#  K78 #
-OcPr -cPr  -OcPr -cPr

K79#  K79 #
-OCH2cPr -cPr  -OCH2cPr -cPr

K80#  K80 #
-OCHCF2 -cPr  -OCHCF2 -cPr

K81#  K81 #
-OCF3 -cPr  -OCF3 -cPr

K82#  K82 #
-OCH2CF3 -cPr  -OCH2CF3 -cPr

K83#  K83 #
-OCH2CH2F -cPr  -OCH2CH2F -cPr

K84#  K84 #
-OCH2CH2OMe -cPr  -OCH2CH2OMe -cPr

K85#  K85 #
-OCH2CH2NMe2 -cPr  -OCH2CH2NMe2 -cPr

K86#  K86 #
-F -cPr  -F -cPr

K87#  K87 #
-Cl -cPr  -Cl -cPr

K88#  K88 #
-Br -cPr  -Br -cPr

K89#  K89 #
-I -cPr  -I -cPr

K90a#  K90a #
-2Py -cPr  -2Py -cPr

K90b#  K90b #
-3Py -cPr  -3Py -cPr

K90c#  K90c #
-4Py -cPr  -4Py -cPr

No  Do not
-R“ -R 2  -R “-R 2

K31  K31
-H -iPr  -H -iPr

K32  K32
-Me -iPr  -Me -iPr

K33  K33
-Et -iPr  -Et -iPr

K34  K34
-nPr -iPr  -nPr -iPr

K35  K35
-iPr -iPr  -iPr -iPr

K36#  K36 #
-cPr -iPr  -cPr -iPr

K37#  K37 #
-cBu -iPr  -cBu -iPr

K38#  K38 #
-O -iPr  -OR -iPr

K39#  K39 #
-iPr    -iPr

K40#  K40 #
-C° -iPr  -C ° -iPr

K41  K41
-cf3 -iPr  -cf3 -iPr

K42#  K42 #
-CN -iPr  -CN -iPr

K43#  K43 #
-Ph -iPr  -Ph -iPr

K44  K44
-OMe -iPr  -OMe -iPr

K45  K45
-OEt -iPr  -OEt -iPr

K46  K46
-OnPr -iPr  -OnPr -iPr

K47  K47
-OiPr -iPr  -OiPr -iPr

K48#  K48 #
-OcPr -iPr  -OcPr -iPr

K49#  K49 #
-OCH2cPr -iPr  -OCH2cPr -iPr

K50  K50
-OCHCF2 -iPr  -OCHCF2 -iPr

K51  K51
-OCF3 -iPr  -OCF3 -iPr

K52  K52
-OCH2CF3 -iPr  -OCH2CF3 -iPr

K53  K53
-OCH2CH2F -iPr  -OCH2CH2F -iPr

K54#  K54 #
-OCH2CH2OMe -iPr  -OCH2CH2OMe -iPr

K55#  K55 #
-OCH2CH2NMe2 -iPr  -OCH2CH2NMe2 -iPr

K56  K56
-F -iPr  -F -iPr

K57  K57
-Cl -iPr  -Cl -iPr

K58  K58
-Br -iPr  -Br -iPr

K59  K59
-I -iPr  -I -iPr

K60a#  K60a #
-2Py -iPr  -2Py -iPr

K60b#  K60b #
-3Py -iPr  -3Py -iPr

K60c#  K60c #
-4Py -iPr  -4Py -iPr

No  Do not
-R11 -R12  -R11 -R12

Kl#  Kl #
-H -nPr  -H -nPr

K2#  K2 #
-Me -nPr  -Me -nPr

K3#  K3 #
-Et -nPr  -Et -nPr

K4#  K4 #
-nPr -nPr  -nPr -nPr

K5#  K5 #
-iPr -nPr  -iPr -nPr

K6#  K6 #
-cPr -nPr  -cPr -nPr

K7#  K7 #
-cBu -nPr  -cBu -nPr

K8#  K8 #
-nPr    -nPr

K9#  K9 #
-nPr    -nPr

K10#  K10 #
O -nPr  O -nPr

Kl 1#  Kl 1 #
-cf3 -nPr  -cf3 -nPr

K12#  K12 #
-CN -nPr  -CN -nPr

K13#  K13 #
-Ph -nPr  -Ph -nPr

K14#  K14 #
-OMe -nPr  -OMe -nPr

K15#  K15 #
-OEt -nPr  -OEt -nPr

K16#  K16 #
-OnPr -nPr  -OnPr -nPr

K17#  K17 #
-OiPr -nPr  -OiPr -nPr

K18#  K18 #
-OcPr -nPr  -OcPr -nPr

K19#  K19 #
-OCHzcPr -nPr  -OCHzcPr -nPr

K20#  K20 #
-OCHCF2 -nPr  -OCHCF2 -nPr

K21#  K21 #
-OCF3 -nPr  -OCF3 -nPr

K22#  K22 #
-OCH2CF3 -nPr  -OCH2CF3 -nPr

K23#  K23 #
-OCH2CH2F -nPr  -OCH2CH2F -nPr

K24#  K24 #
-OCH2CH2OMe -nPr  -OCH2CH2OMe -nPr

K25#  K25 #
-OCH2CH2NMe2 -nPr  -OCH2CH2NMe2 -nPr

K26#  K26 #
-F -nPr  -F -nPr

K27#  K27 #
-Cl -nPr  -Cl -nPr

K28#  K28 #
-Br -nPr  -Br -nPr

K29#  K29 #
-I -nPr  -I -nPr

K30a#  K30a #
-2Py -nPr  -2Py -nPr

K30b#  K30b #
-3Py -nPr  -3Py -nPr

K30c#  K30c #
-4Py -nPr  -4Py -nPr

imagen153image153

No  Do not
-R11 R12  -R11 R12

L61#  L61 #
-H -I  -H -I

L62#  L62 #
-Me -I  -Me -I

L63#  L63 #
-Et -I  -Et -I

L64#  L64 #
-nPr -I  -nPr -I

L65#  L65 #
-iPr -I  -iPr -I

L66#  L66 #
-cPr -I  -cPr -I

L67#  L67 #
-cBu -I  -cBu -I

L68#  L68 #
-0 -I  -0 -I

L69#  L69 #
-I    -I

L70#  L70 #
-I    -I

L71#  L71 #
-cf3 -I  -cf3 -I

L72#  L72 #
-CN -I  -CN -I

L73#  L73 #
-Ph -I  -Ph -I

L74#  L74 #
-OMe -I  -OMe -I

L75#  L75 #
-OEt -I  -OEt -I

L76#  L76 #
-OnPr -I  -OnPr -I

L77#  L77 #
-OiPr -I  -OiPr -I

L78#  L78 #
-OcPr -I  -OcPr -I

L79#  L79 #
-OCH2cPr -I  -OCH2cPr -I

L80#  L80 #
-OCHCF2 -I  -OCHCF2 -I

L81#  L81 #
-OCF3 -I  -OCF3 -I

L82#  L82 #
-OCH2CF3 -I  -OCH2CF3 -I

L83#  L83 #
-OCH2CH2F -I  -OCH2CH2F -I

L84#  L84 #
-OCH2CH2OMe -I  -OCH2CH2OMe -I

L85#  L85 #
-OCH2CH2NMe2 -I  -OCH2CH2NMe2 -I

L86#  L86 #
-F -I  -F -I

L87#  L87 #
-Cl -I  -Cl -I

L88#  L88 #
-Br -I  -Br -I

L89#  L89 #
-I -I  -I -I

L90a#  L90a #
-2Py -I  -2Py -I

L90b#  L90b #
-3Py -I  -3Py -I

L90c#  L90c #
-4Py -I  -4Py -I

No  Do not
-R11 R12  -R11 R12

L31#  L31 #
-H -Br  -H -Br

L32#  L32 #
-Me -Br  -Me -Br

L33#  L33 #
-Et -Br  -Et -Br

L34#  L34 #
-nPr -Br  -nPr -Br

L35#  L35 #
-iPr -Br  -iPr -Br

L36#  L36 #
-cPr -Br  -cPr -Br

L37#  L37 #
-cBu -Br  -cBu -Br

L38#  L38 #
-O -Br  -OR -Br

L39#  L39 #
-O -Br  -OR -Br

L40#  L40 #
-O -Br  -OR -Br

L41#  L41 #
-cf3 -Br  -cf3 -Br

L42#  L42 #
-CN -Br  -CN -Br

L43#  L43 #
-Ph -Br  -Ph -Br

L44#  L44 #
-OMe -Br  -OMe -Br

L45#  L45 #
-OEt -Br  -OEt -Br

L46#  L46 #
-OnPr -Br  -OnPr -Br

L47#  L47 #
-OiPr -Br  -OiPr -Br

L48#  L48 #
-OcPr -Br  -OcPr -Br

L49#  L49 #
-OCH2cPr -Br  -OCH2cPr -Br

L50#  L50 #
-OCHCFz -Br  -OCHCFz -Br

L51#  L51 #
-OCF3 -Br  -OCF3 -Br

L52#  L52 #
-OCH2CF3 -Br  -OCH2CF3 -Br

L53#  L53 #
-OCH2CH2F -Br  -OCH2CH2F -Br

L54#  L54 #
-OCH2CH2OMe -Br  -OCH2CH2OMe -Br

L55#  L55 #
-OCH2CH2NMe2 -Br  -OCH2CH2NMe2 -Br

L56#  L56 #
-F -Br  -F -Br

L57#  L57 #
-Cl -Br  -Cl -Br

L58#  L58 #
-Br -Br  -Br -Br

L59#  L59 #
-I -Br  -I -Br

L60a#  L60a #
-2Py -Br  -2Py -Br

L60b#  L60b #
-3Py -Br  -3Py -Br

L60c#  L60c #
-4Py -Br  -4Py -Br

No  Do not
-R11 -R12  -R11 -R12

LI  LI
-H -Cl  -H -Cl

L2  L2
-Me -Cl  -Me -Cl

L3  L3
-Et -Cl  -Et -Cl

L4  L4
-nPr -Cl  -nPr -Cl

L5  L5
-iPr -Cl  -iPr -Cl

L6#  L6 #
-cPr -Cl  -cPr -Cl

L7#  L7 #
-cBu -Cl  -cBu -Cl

L8#  L8 #
-Cl    -Cl

L9#  L9 #
-Cl    -Cl

L10#  L10 #
-0> -Cl  -0> -Cl

LI 1  LI 1
-cf3 -Cl  -cf3 -Cl

L12#  L12 #
-CN -Cl  -CN -Cl

L13#  L13 #
-Ph -Cl  -Ph -Cl

L14  L14
-OMe -Cl  -OMe -Cl

L15  L15
-OEt -Cl  -OEt -Cl

L16  L16
-OnPr -Cl  -OnPr -Cl

L17  L17
-OiPr -Cl  -OiPr -Cl

L18#  L18 #
-OcPr -Cl  -OcPr -Cl

LI 9#  LI 9 #
-OCH2cPr -Cl  -OCH2cPr -Cl

L20  L20
-OCHCF2 -Cl  -OCHCF2 -Cl

L21  L21
-OCF3 -Cl  -OCF3 -Cl

L22  L22
-OCH2CF3 -Cl  -OCH2CF3 -Cl

L23  L23
-OCH2CH2F -Cl  -OCH2CH2F -Cl

L24#  L24 #
-OCH2CH2OMe -Cl  -OCH2CH2OMe -Cl

L25#  L25 #
-OCH2CH2NMe2 -Cl  -OCH2CH2NMe2 -Cl

L26  L26
-F -Cl  -F -Cl

L27  L27
-Cl -Cl  -Cl -Cl

L28  L28
-Br -Cl  -Br -Cl

L29  L29
-I -Cl  -I -Cl

L30a#  L30a #
-2Py -Cl  -2Py -Cl

L30b#  L30b #
-3Py -Cl  -3Py -Cl

L30c#  L30c #
-4Py -Cl  -4Py -Cl

imagen154image154

No  Do not
-R" -R12  -R "-R12

M61  M61
-H -Et  -H -Et

M62  M62
-Me -Et  -Me -Et

M63  M63
-Et -Et  -Et -Et

M64  M64
-nPr -Et  -nPr -Et

M65  M65
-iPr -Et  -iPr -Et

M66  M66
-cPr -Et  -cPr -Et

M67  M67
-cBu -Et  -cBu -Et

M68  M68
-0 -Et  -0 -Et

M69  M69
-o -Et  -o -Et

M70  M70
-Et    -Et

M71  M71
-cf3 -Et  -cf3 -Et

M72  M72
-CN -Et  -CN -Et

M73  M73
-Ph -Et  -Ph -Et

M74  M74
-OMe -Et  -OMe -Et

M75  M75
-OEt -Et  -OEt -Et

M76  M76
-OnPr -Et  -OnPr -Et

M77  M77
-OiPr -Et  -OiPr -Et

M78  M78
-OcPr -Et  -OcPr -Et

M79  M79
-OCH2cPr -Et  -OCH2cPr -Et

M80  M80
-ochcf2 -Et  -ochcf2 -Et

M81  M81
-ocf3 -Et  -ocf3 -Et

M82  M82
-och2cf3 -Et  -och2cf3 -Et

M83  M83
-och2ch2f -Et  -och2ch2f -Et

M84  M84
-OCH2CH2OMe -Et  -OCH2CH2OMe -Et

M85  M85
-OCH2CH2NMe2 -Et  -OCH2CH2NMe2 -Et

M86  M86
-F -Et  -F -Et

M87  M87
-Cl -Et  -Cl -Et

M88  M88
-Br -Et  -Br -Et

M89  M89
-I -Et  -I -Et

M90a  M90a
-2Py -Et  -2Py -Et

M90b  M90b
-3Py -Et  -3Py -Et

M90c  M90c
-4Py -Et  -4Py -Et

No  Do not
-R" -R12  -R "-R12

M31#  M31 #
-H -Me  -H -Me

M3 2#  M3 2 #
-Me -Me  -Me -Me

M3 3#  M3 3 #
-Et -Me  -Et -Me

M3 4#  M3 4 #
-nPr -Me  -nPr -Me

M3 5#  M3 5 #
-iPr -Me  -iPr -Me

M3 6#  M3 6 #
-cPr -Me  -cPr -Me

M3 7#  M3 7 #
-cBu -Me  -cBu -Me

M3 8#  M3 8 #
-0 -Me  -0 -Me

M3 9#  M3 9 #
-o -Me  -or -Me

M40#  M40 #
-Me    -I

M41#  M41 #
-cf3 -Me  -cf3 -Me

M42#  M42 #
-CN -Me  -CN -Me

M43#  M43 #
-Ph -Me  -Ph -Me

M44#  M44 #
-OMe -Me  -OMe -Me

M45#  M45 #
-OEt -Me  -OEt -Me

M46#  M46 #
-OnPr -Me  -OnPr -Me

M47#  M47 #
-OiPr -Me  -OiPr -Me

M48#  M48 #
-OcPr -Me  -OcPr -Me

M49#  M49 #
-OCH2cPr -Me  -OCH2cPr -Me

M50#  M50 #
-ochcf2 -Me  -ochcf2 -Me

M51#  M51 #
-ocf3 -Me  -ocf3 -Me

M52#  M52 #
-och2cf3 -Me  -och2cf3 -Me

M53#  M53 #
-och2ch2f -Me  -och2ch2f -Me

M54#  M54 #
-OCH2CH2OMe -Me  -OCH2CH2OMe -Me

M55#  M55 #
-OCH2CH2NMe2 -Me  -OCH2CH2NMe2 -Me

M56#  M56 #
-F -Me  -F -Me

M57#  M57 #
-Cl -Me  -Cl -Me

M58#  M58 #
-Br -Me  -Br -Me

M59#  M59 #
-I -Me  -I -Me

M60a#  M60a #
-2Py -Me  -2Py -Me

M60b#  M60b #
-3Py -Me  -3Py -Me

M60c#  M60c #
-4Py -Me  -4Py -Me

No  Do not
-R“ -R12  -R “-R12

Ml#  Ml #
-H -H  -H H

M2#  M2 #
-Me -H  -Me -H

M3#  M3 #
-Et -H  -Et -H

M4#  M4 #
-nPr -H  -nPr -H

M5#  M5 #
-iPr -H  -iPr -H

M6#  M6 #
-cPr -H  -cPr -H

M7#  M7 #
-cBu -H  -cBu -H

M8#  M8 #
-H    -H

M9#  M9 #
-H    -H

M10#  M10 #
-o -H  -o -H

Mil#  One thousand#
-cf3 -H  -cf3 -H

Ml 2#  Ml 2 #
-CN -H  -CN -H

M13#  M13 #
-Ph -H  -Ph -H

M14#  M14 #
-OMe -H  -OMe -H

Ml 5#  Ml 5 #
-OEt -H  -OEt -H

Ml 6#  Ml 6 #
-OnPr -H  -OnPr -H

Ml 7#  Ml 7 #
-OiPr -H  -OiPr -H

Ml 8#  Ml 8 #
-OcPr -H  -OcPr -H

Ml 9#  Ml 9 #
-OCH2cPr -H  -OCH2cPr -H

M20#  M20 #
-ochcf2 -H  -ochcf2 -H

M21#  M21 #
-ocf3 -H  -ocf3 -H

M22#  M22 #
-och2cf3 -H  -och2cf3 -H

M23#  M23 #
-och2ch2f -H  -och2ch2f -H

M24#  M24 #
-OCH2CH2OMe -H  -OCH2CH2OMe -H

M25#  M25 #
-OCH2CH2NMe2 -H  -OCH2CH2NMe2 -H

M2 6#  M2 6 #
-F -H  -F -H

M27#  M27 #
-Cl -H  -Cl -H

M28#  M28 #
-Br -H  -Br -H

M2 9#  M2 9 #
-I -H  -I -H

M30a#  M30a #
-2Py -H  -2Py -H

M3 Ob#  M3 Ob #
-3Py -H  -3Py -H

M30c#  M30c #
-4Py -H  -4Py -H

(# no es parte de la invention)(# is not part of the invention)

imagen155image155

imagen156image156

No  Do not
-R11 -R12  -R11 -R12

031#  031 #
-H -Br  -H -Br

032#  032 #
-Me -Br  -Me -Br

033#  033 #
-Et -Br  -Et -Br

034#  034 #
-nPr -Br  -nPr -Br

035#  035 #
-iPr -Br  -iPr -Br

036#  036 #
-cPr -Br  -cPr -Br

037#  037 #
-cBu -Br  -cBu -Br

038#  038 #
-o -Br  -or -Br

039#  039 #
-Br    -Br

040#  040 #
-Br    -Br

041#  041 #
-cf3 -Br  -cf3 -Br

042#  042 #
-CN -Br  -CN -Br

043#  043 #
-Ph -Br  -Ph -Br

044#  044 #
-OMe -Br  -OMe -Br

045#  045 #
-OEt -Br  -OEt -Br

046#  046 #
-OnPr -Br  -OnPr -Br

047#  047 #
-OiPr -Br  -OiPr -Br

048#  048 #
-OcPr -Br  -OcPr -Br

049#  049 #
-OCH2cPr -Br  -OCH2cPr -Br

050#  050 #
-OCHCF2 -Br  -OCHCF2 -Br

051#  051 #
-OCF3 -Br  -OCF3 -Br

052#  052 #
-OCH2CF3 -Br  -OCH2CF3 -Br

053#  053 #
-OCH2CH2F -Br  -OCH2CH2F -Br

054#  054 #
-OCH2CH2OMe -Br  -OCH2CH2OMe -Br

055#  055 #
-OCH2CH2NMe2 -Br  -OCH2CH2NMe2 -Br

056#  056 #
-F -Br  -F -Br

057#  057 #
-Cl -Br  -Cl -Br

058#  058 #
-Br -Br  -Br -Br

059#  059 #
-I -Br  -I -Br

O60a#  O60a #
-2Py -Br  -2Py -Br

O60b#  O60b #
-3Py -Br  -3Py -Br

O60c#  O60c #
-4Py -Br  -4Py -Br

No  Do not
-R11 -R12  -R11 -R12

Ol  Ol
-H -Cl  -H -Cl

02  02
-Me -Cl  -Me -Cl

03  03
■Et -Cl  ■ Et -Cl

04  04
-nPr -Cl  -nPr -Cl

05  05
-iPr -Cl  -iPr -Cl

06#  06 #
-cPr -Cl  -cPr -Cl

07#  07 #
-cBu -Cl  -cBu -Cl

08#  08 #
-0 -Cl  -0 -Cl

09#  09 #
-0 -Cl  -0 -Cl

OlO#  OlO #
-Cl    -Cl

Oil  Oil
-CF3 -Cl  -CF3 -Cl

012#  012 #
-CN -Cl  -CN -Cl

013#  013 #
-Ph -Cl  -Ph -Cl

014  014
-OMe -Cl  -OMe -Cl

015  015
-OEt -Cl  -OEt -Cl

016  016
-OnPr -Cl  -OnPr -Cl

017  017
-OiPr -Cl  -OiPr -Cl

018#  018 #
-OcPr -Cl  -OcPr -Cl

019#  019 #
-OCH2cPr -Cl  -OCH2cPr -Cl

020  020
-OCHCF2 -Cl  -OCHCF2 -Cl

021  021
-OCF3 -Cl  -OCF3 -Cl

022  022
-OCH2CF3 -Cl  -OCH2CF3 -Cl

023  023
-OCH2CH2F -Cl  -OCH2CH2F -Cl

024#  024 #
-OCH2CH2OMe -Cl  -OCH2CH2OMe -Cl

025#  025 #
-OCH2CH2NMe2 -Cl  -OCH2CH2NMe2 -Cl

026  026
-F -Cl  -F -Cl

027  027
-Cl -Cl  -Cl -Cl

028  028
-Br -Cl  -Br -Cl

029  029
-I -Cl  -I -Cl

03 Oa#  03 Oa #
-2Py -Cl  -2Py -Cl

03 Ob#  03 Ob #
-3Py -Cl  -3Py -Cl

03 Oc#  03 Oc #
-4Py -Cl  -4Py -Cl

No  Do not
-R" -Ru  -R "-Ru

061#  061 #
-H -I  -H -I

062#  062 #
-Me -I  -Me -I

063#  063 #
-Et -I  -Et -I

064#  064 #
-nPr -I  -nPr -I

065#  065 #
-iPr -I  -iPr -I

066#  066 #
-cPr -I  -cPr -I

067#  067 #
-cBu -I  -cBu -I

068#  068 #
-I    -I

069#  069 #
-I    -I

070#  070 #
-G> -I  -G> -I

071#  071 #
-cf3 -I  -cf3 -I

072#  072 #
-CN -I  -CN -I

073#  073 #
-Ph -I  -Ph -I

074#  074 #
-OMe -I  -OMe -I

075#  075 #
-OEt -I  -OEt -I

076#  076 #
-OnPr -1  -OnPr -1

077#  077 #
-OiPr -I  -OiPr -I

078#  078 #
-OcPr -I  -OcPr -I

079#  079 #
-OCH2cPr -I  -OCH2cPr -I

080#  080 #
-OCHCF2 -I  -OCHCF2 -I

081#  081 #
-OCF3 -I  -OCF3 -I

082#  082 #
-OCH2CF3 -I  -OCH2CF3 -I

083#  083 #
-OCH2CH2F -I  -OCH2CH2F -I

084#  084 #
-OCH2CH2OMe -I  -OCH2CH2OMe -I

085#  085 #
-OCH2CH2NMe2 -I  -OCH2CH2NMe2 -I

086#  086 #
-F -I  -F -I

087#  087 #
-Cl -I  -Cl -I

088#  088 #
-Br -I  -Br -I

089#  089 #
-I -I  -I -I

O90a#  O90a #
-2Py -I  -2Py -I

O90b#  O90b #
-3Py -I  -3Py -I

O90c#  O90c #
-4Py -I  -4Py -I

imagen157image157

No  Do not
-R"  -R "

P61  P61
-H -Et  -H -Et

P62  P62
-Me -Et  -Me -Et

P63  P63
-Et -Et  -Et -Et

P64  P64
-nPr -Et  -nPr -Et

P65  P65
-iPr -Et  -iPr -Et

P66#  P66 #
-cPr -Et  -cPr -Et

P67#  P67 #
-cBu -Et  -cBu -Et

P68#  P68 #
-Et    -Et

P69#  P69 #
-O -Et  -OR -Et

P70#  P70 #
-Et    -Et

P71  P71
-cf3 -Et  -cf3 -Et

P72#  P72 #
-CN -Et  -CN -Et

P73#  P73 #
-Ph -Et  -Ph -Et

P74  P74
-OMe -Et  -OMe -Et

P75  P75
-OEt -Et  -OEt -Et

P76  P76
-OnPr -Et  -OnPr -Et

P77  P77
-OiPr -Et  -OiPr -Et

P78#  P78 #
-OcPr -Et  -OcPr -Et

P79#  P79 #
-OCH2cPr -Et  -OCH2cPr -Et

P80  P80
-OCHCF2 -Et  -OCHCF2 -Et

P81  P81
-OCF3 -Et  -OCF3 -Et

P82  P82
-OCH2CF3 -Et  -OCH2CF3 -Et

P83  P83
-OCH2CH2F -Et  -OCH2CH2F -Et

P84#  P84 #
-OCH2CH2OMe -Et  -OCH2CH2OMe -Et

P85#  P85 #
-OCH2CH2NMe2 -Et  -OCH2CH2NMe2 -Et

P86  P86
-F -Et  -F -Et

P87  P87
-Cl -Et  -Cl -Et

P88  P88
-Br -Et  -Br -Et

P89  P89
-I -Et  -I -Et

P90a#  P90a #
-2Py -Et  -2Py -Et

P90b#  P90b #
-3Py -Et  -3Py -Et

P90c#  P90c #
-4Py -Et  -4Py -Et

No  Do not
-Ru  -Ru

P31#  P31 #
-H -Me  -H -Me

P32#  P32 #
-Me -Me  -Me -Me

P33#  P33 #
-Et -Me  -Et -Me

P34#  P34 #
-nPr -Me  -nPr -Me

P35#  P35 #
-iPr -Me  -iPr -Me

P36#  P36 #
-cPr -Me  -cPr -Me

P37#  P37 #
-cBu -Me  -cBu -Me

P38#  P38 #
-O -Me  -OR -Me

P39#  P39 #
-O -Me  -OR -Me

P40#  P40 #
-Me    -I

P41#  P41 #
-cf3 -Me  -cf3 -Me

P42#  P42 #
-CN -Me  -CN -Me

P43#  P43 #
-Ph -Me  -Ph -Me

P44#  P44 #
-OMe -Me  -OMe -Me

P45#  P45 #
-OEt -Me  -OEt -Me

P46#  P46 #
-OnPr -Me  -OnPr -Me

P47#  P47 #
-OiPr -Me  -OiPr -Me

P48#  P48 #
-OcPr -Me  -OcPr -Me

P49#  P49 #
-OCH2cPr -Me  -OCH2cPr -Me

P50#  P50 #
-OCHCF2 -Me  -OCHCF2 -Me

P51#  P51 #
-OCF3 -Me  -OCF3 -Me

P52#  P52 #
-OCH2CF3 -Me  -OCH2CF3 -Me

P53#  P53 #
-OCH2CH2F -Me  -OCH2CH2F -Me

P54#  P54 #
-OCH2CH2OMe -Me  -OCH2CH2OMe -Me

P55#  P55 #
-OCH2CH2NMe2 -Me  -OCH2CH2NMe2 -Me

P56#  P56 #
-F -Me  -F -Me

P57#  P57 #
-Cl -Me  -Cl -Me

P58#  P58 #
-Br -Me  -Br -Me

P59#  P59 #
-I -Me  -I -Me

P60a#  P60a #
-2Py -Me  -2Py -Me

P60b#  P60b #
-3Py -Me  -3Py -Me

P60c#  P60c #
-4Py -Me  -4Py -Me

No  Do not
-R11 nr  -R11 nr

PI#  PI#
-H -H  -H H

P2#  P2 #
-Me -H  -Me -H

P3#  P3 #
-Et -H  -Et -H

P4#  P4 #
-nPr -H  -nPr -H

P5#  P5 #
-iPr -H  -iPr -H

P6#  P6 #
-cPr -H  -cPr -H

P7#  P7 #
-cBu -H  -cBu -H

P8#  P8 #
-O -H  -OR -H

P9#  P9 #
-H    -H

P10#  P10 #
O -H  O -H

PI 1#  PI 1 #
-cf3 -H  -cf3 -H

P12#  P12 #
-CN -H  -CN -H

P13#  P13 #
-Ph -H  -Ph -H

P14#  P14 #
-OMe -H  -OMe -H

P15#  P15 #
-OEt -H  -OEt -H

P16#  P16 #
-OnPr -H  -OnPr -H

P17#  P17 #
-OiPr -H  -OiPr -H

P18#  P18 #
-OcPr -H  -OcPr -H

P19#  P19 #
-OCH2cPr -H  -OCH2cPr -H

P20#  P20 #
-OCHCF2 -H  -OCHCF2 -H

P21#  P21 #
-OCF3 -H  -OCF3 -H

P22#  P22 #
-OCH2CF3 -H  -OCH2CF3 -H

P23#  P23 #
-OCH2CH2F -H  -OCH2CH2F -H

P24#  P24 #
-OCH2CH2OMe -H  -OCH2CH2OMe -H

P25#  P25 #
-OCH2CH2NMe2 -H  -OCH2CH2NMe2 -H

P26#  P26 #
-F -H  -F -H

P27#  P27 #
-Cl -H  -Cl -H

P28#  P28 #
-Br -H  -Br -H

P29#  P29 #
-I -H  -I -H

P30a#  P30a #
-2Py -H  -2Py -H

P30b#  P30b #
-3Py -H  -3Py -H

P30c#  P30c #
-4Py -H  -4Py -H

imagen158image158

No  Do not
-R11 -R12  -R11 -R12

Q61#  Q61 #
-H -cPr  -H -cPr

062#  062 #
-Me -cPr  -Me -cPr

Q63#  Q63 #
-Et -cPr  -Et -cPr

064#  064 #
-nPr -cPr  -nPr -cPr

065#  065 #
-iPr -cPr  -iPr -cPr

066#  066 #
-cPr -cPr  -cPr -cPr

Q67#  Q67 #
-cBu -cPr  -cBu -cPr

Q68#  Q68 #
-cPr    -cPr

Q69#  Q69 #
-o -cPr  -o -cPr

Q70#  Q70 #
-cPr    -cPr

071#  071 #
-cf3 -cPr  -cf3 -cPr

Q72#  Q72 #
-CN -cPr  -CN -cPr

Q73#  Q73 #
-Ph -cPr  -Ph -cPr

Q74#  Q74 #
-OMe -cPr  -OMe -cPr

Q75#  Q75 #
-OEt -cPr  -OEt -cPr

076#  076 #
-OnPr -cPr  -OnPr -cPr

Q77#  Q77 #
-OiPr -cPr  -OiPr -cPr

Q78#  Q78 #
-OcPr -cPr  -OcPr -cPr

Q79#  Q79 #
-OCH2cPr -cPr  -OCH2cPr -cPr

Q80#  Q80 #
-ochcf2 -cPr  -ochcf2 -cPr

Q81#  Q81 #
-ocf3 -cPr  -ocf3 -cPr

Q82#  Q82 #
-och2cf3 -cPr  -och2cf3 -cPr

Q83#  Q83 #
-och2ch2f -cPr  -och2ch2f -cPr

Q84#  Q84 #
-OCH2CH2OMe -cPr  -OCH2CH2OMe -cPr

Q85#  Q85 #
-OCH2CH2NMe2 -cPr  -OCH2CH2NMe2 -cPr

086#  086 #
-F -cPr  -F -cPr

087#  087 #
-Cl -cPr  -Cl -cPr

088#  088 #
-Br -cPr  -Br -cPr

089#  089 #
-I -cPr  -I -cPr

Q90a#  Q90a #
-2Py -cPr  -2Py -cPr

Q90b#  Q90b #
-3Py -cPr  -3Py -cPr

Q90c#  Q90c #
-4Py -cPr  -4Py -cPr

No  Do not
-R“ -R12  -R “-R12

Q31  Q31
-H -iPr  -H -iPr

Q32  Q32
-Me -iPr  -Me -iPr

Q33  Q33
-Et -iPr  -Et -iPr

Q34  Q34
-nPr -iPr  -nPr -iPr

Q35  Q35
-iPr -iPr  -iPr -iPr

Q36#  Q36 #
-cPr -iPr  -cPr -iPr

Q37#  Q37 #
-cBu -iPr  -cBu -iPr

Q38#  Q38 #
-0 -iPr  -0 -iPr

Q39#  Q39 #
-o -iPr  -o -iPr

Q40#  Q40 #
-o> -iPr  -o> -iPr

041  041
-cf3 -iPr  -cf3 -iPr

Q42#  Q42 #
-CN -iPr  -CN -iPr

Q43#  Q43 #
-Ph -iPr  -Ph -iPr

044  044
-OMe -iPr  -OMe -iPr

Q45  Q45
-OEt -iPr  -OEt -iPr

Q46  Q46
-OnPr -iPr  -OnPr -iPr

Q47  Q47
-OiPr -iPr  -OiPr -iPr

Q48#  Q48 #
-OcPr -iPr  -OcPr -iPr

Q49#  Q49 #
-OCH2cPr -iPr  -OCH2cPr -iPr

050  050
-ochcf2 -iPr  -ochcf2 -iPr

Q51  Q51
-ocf3 -iPr  -ocf3 -iPr

Q52  Q52
-och2cf3 -iPr  -och2cf3 -iPr

Q53  Q53
-och2ch2f -iPr  -och2ch2f -iPr

Q54#  Q54 #
-OCH2CH2OMe -iPr  -OCH2CH2OMe -iPr

Q55#  Q55 #
-OCH2CH2NMe2 -iPr  -OCH2CH2NMe2 -iPr

056  056
-F -iPr  -F -iPr

Q57  Q57
-Cl -iPr  -Cl -iPr

058  058
-Br -iPr  -Br -iPr

059  059
-I -iPr  -I -iPr

Q60a#  Q60a #
-2Py -iPr  -2Py -iPr

Q60b#  Q60b #
-3Py -iPr  -3Py -iPr

Q6 Oc#  Q6 Oc #
-4Py -iPr  -4Py -iPr

No  Do not
-R“ -R12  -R “-R12

01#  01 #
-H -nPr  -H -nPr

Q2#  Q2 #
-Me -nPr  -Me -nPr

Q3#  Q3 #
-Et -nPr  -Et -nPr

Q4#  Q4 #
-nPr -nPr  -nPr -nPr

Q5#  Q5 #
-iPr -nPr  -iPr -nPr

Q6#  Q6 #
-cPr -nPr  -cPr -nPr

Q7#  Q7 #
-cBu -nPr  -cBu -nPr

Q8#  Q8 #
-nPr    -nPr

Q9#  Q9 #
-o -nPr  -o -nPr

Q10#  Q10 #
-nPr    -nPr

on#  on #
-cf3 -nPr  -cf3 -nPr

Q12#  Q12 #
-CN -nPr  -CN -nPr

Q13#  Q13 #
-Ph -nPr  -Ph -nPr

Q14#  Q14 #
-OMe -nPr  -OMe -nPr

015#  015 #
-OEt -nPr  -OEt -nPr

016#  016 #
-OnPr -nPr  -OnPr -nPr

Q17#  Q17 #
-OiPr -nPr  -OiPr -nPr

Q18#  Q18 #
-OcPr -nPr  -OcPr -nPr

Q19#  Q19 #
-OCH2cPr -nPr  -OCH2cPr -nPr

Q20#  Q20 #
-ochcf2 -nPr  -ochcf2 -nPr

Q21#  Q21 #
-ocf3 -nPr  -ocf3 -nPr

Q22#  Q22 #
-och2cf3 -nPr  -och2cf3 -nPr

Q23#  Q23 #
-och2ch2f -nPr  -och2ch2f -nPr

Q24#  Q24 #
-OCH2CH2OMe -nPr  -OCH2CH2OMe -nPr

Q25#  Q25 #
-OCH2CH2NMe2 -nPr  -OCH2CH2NMe2 -nPr

Q26#  Q26 #
-F -nPr  -F -nPr

Q27#  Q27 #
-Cl -nPr  -Cl -nPr

028#  028 #
-Br -nPr  -Br -nPr

029#  029 #
-I -nPr  -I -nPr

Q30a#  Q30a #
-2Py -nPr  -2Py -nPr

Q30b#  Q30b #
-3Py -nPr  -3Py -nPr

Q30c#  Q30c #
-4Py -nPr  -4Py -nPr

imagen159image159

No  Do not
-R11 -R12  -R11 -R12

R61#  R61 #
-H -I  -H -I

R62#  R62 #
-Me -I  -Me -I

R63#  R63 #
-Et -I  -Et -I

R64#  R64 #
-nPr -I  -nPr -I

R65#  R65 #
-iPr -I  -iPr -I

R66#  R66 #
-cPr -I  -cPr -I

R67#  R67 #
-cBu -I  -cBu -I

R68#  R68 #
-0 -I  -0 -I

R69#  R69 #
-o -I  -or -I

R70#  R70 #
-o> -I  -o> -I

R71#  R71 #
-cf3 -I  -cf3 -I

R72#  R72 #
■ -CN . -I  ■ -CN. -I

R73#  R73 #
-Ph -I  -Ph -I

R74#  R74 #
-OMe -I  -OMe -I

R75#  R75 #
-OEt -I  -OEt -I

R76#  R76 #
-OnPr -I  -OnPr -I

R77#  R77 #
-OiPr -1  -OiPr -1

R78#  R78 #
-OcPr -I  -OcPr -I

R79#  R79 #
-OCH2cPr -I  -OCH2cPr -I

R80#  R80 #
-OCHCF2 -I  -OCHCF2 -I

R81#  R81 #
-OCF3 -I  -OCF3 -I

R82#  R82 #
-OCH2CF3 -I  -OCH2CF3 -I

R83#  R83 #
-OCH2CH2F -I  -OCH2CH2F -I

R84#  R84 #
-OCH2CH2OMe -I  -OCH2CH2OMe -I

R85#  R85 #
-OCH2CH2NMe2 -I  -OCH2CH2NMe2 -I

R86#  R86 #
-F -I  -F -I

R87#  R87 #
-Cl -I  -Cl -I

R88#  R88 #
-Br -I  -Br -I

R89#  R89 #
-I -I  -I -I

R90a#  R90a #
-2Py -I  -2Py -I

R90b#  R90b #
-3Py -I  -3Py -I

R90c#  R90c #
-4Py -I  -4Py -I

No  Do not
-R11 R12  -R11 R12

R31#  R31 #
-H -Br  -H -Br

R32#  R32 #
-Me -Br  -Me -Br

R33#  R33 #
-Et -Br  -Et -Br

R34#  R34 #
-nPr -Br  -nPr -Br

R35#  R35 #
-iPr -Br  -iPr -Br

R36#  R36 #
-cPr -Br  -cPr -Br

R37#  R37 #
-cBu -Br  -cBu -Br

R38#  R38 #
-Br    -Br

R39#  R39 #
-O -Br  -OR -Br

R40#  R40 #
-Q -Br  -Q -Br

R41#  R41 #
-cf3 -Br  -cf3 -Br

R42#  R42 #
-CN -Br  -CN -Br

R43#  R43 #
-Ph -Br  -Ph -Br

R44#  R44 #
-OMe -Br  -OMe -Br

R45#  R45 #
-OEt -Br  -OEt -Br

R46#  R46 #
-OnPr -Br  -OnPr -Br

R47#  R47 #
-OiPr -Br  -OiPr -Br

R48#  R48 #
-OcPr -Br  -OcPr -Br

R49#  R49 #
-OCH2cPr -Br  -OCH2cPr -Br

R50#  R50 #
-OCHCF2 -Br  -OCHCF2 -Br

R51#  R51 #
-OCF3 -Br  -OCF3 -Br

R52#  R52 #
-OCH2CF3 -Br  -OCH2CF3 -Br

R53#  R53 #
-OCH2CH2F -Br  -OCH2CH2F -Br

R54#  R54 #
-OCH2CH2OMe -Br  -OCH2CH2OMe -Br

R55#  R55 #
OCH2CH2NMe2 -Br  OCH2CH2NMe2 -Br

R56#  R56 #
-F -Br  -F -Br

R57#  R57 #
-Cl -Br  -Cl -Br

R58#  R58 #
-Br -Br  -Br -Br

R59#  R59 #
-I -Br  -I -Br

R60a#  R60a #
-2Py -Br  -2Py -Br

R60b#  R60b #
-3Py -Br  -3Py -Br

R60c#  R60c #
-4Py -Br  -4Py -Br

No  Do not
-R11 -R12  -R11 -R12

R1  R1
-H -Cl  -H -Cl

R2  R2
-Me -Cl  -Me -Cl

R3  R3
-Et -Cl  -Et -Cl

R4  R4
-nPr -Cl  -nPr -Cl

R5  R5
-iPr -Cl  -iPr -Cl

R6#  R6 #
-cPr -Cl  -cPr -Cl

R7#  R7 #
-cBu -Cl  -cBu -Cl

R8#  R8 #
-0 -Cl  -0 -Cl

R9#  R9 #
-Cl    -Cl

RIO#  RIVER#
-Q -Cl  -Q -Cl

Rll  Rll
-cf3 -Cl  -cf3 -Cl

R12#  R12 #
-CN -Cl  -CN -Cl

R13#  R13 #
-Ph -Cl  -Ph -Cl

R14  R14
-OMe -Cl  -OMe -Cl

R15  R15
-OEt -Cl  -OEt -Cl

R16  R16
-OnPr -Cl  -OnPr -Cl

R17  R17
-OiPr -Cl  -OiPr -Cl

R18#  R18 #
-OcPr -Cl  -OcPr -Cl

R19#  R19 #
-OCH2cPr -Cl  -OCH2cPr -Cl

R20  R20
-OCHCF2 -Cl  -OCHCF2 -Cl

R21  R21
-OCF3 -Cl  -OCF3 -Cl

R22  R22
-OCH2CF3 -Cl  -OCH2CF3 -Cl

R23  R23
-OCH2CH2F -Cl  -OCH2CH2F -Cl

R24#  R24 #
-OCH2CH2OMe -Cl  -OCH2CH2OMe -Cl

R25#  R25 #
-OCH2CH2NMe2 -Cl  -OCH2CH2NMe2 -Cl

R26  R26
-F -Cl  -F -Cl

R27  R27
-Cl -Cl  -Cl -Cl

R28  R28
-Br -Cl  -Br -Cl

R29  R29
-I -Cl  -I -Cl

R30a#  R30a #
-2Py -Cl  -2Py -Cl

R30b#  R30b #
-3Py -Cl  -3Py -Cl

R30c#  R30c #
-4Py -Cl  -4Py -Cl

El compuesto de formula (I) o una sal del mismo tiene actividad inhibidora contra la actividad de cinasa de la protema de fusion EML4-ALK, ademas de actividad inhibidora del crecimiento contra celulas dependientes de la 5 protema de fusion EML4-ALK, y puede usarse como principio activo en composiciones farmaceuticas para prevenir y/o tratar cancer, tal como cancer de pulmon en una realizacion, cancer de pulmon de celulas no pequenas o cancer de pulmon de celulas pequenas en otra realizacion, cancer positivo para los polinucleotidos de fusion ALK en otra realizacion mas, cancer de pulmon positivo para los polinucleotidos de fusion ALK en otra realizacion mas, cancer de pulmon de celulas no pequenas positivo para los polinucleotidos de fusion ALK en otra realizacion mas, cancer 10 positivo para protemas de fusion ALK en otra realizacion mas, cancer de pulmon positivo para protemas de fusion ALK en otra realizacion mas, cancer de pulmon de celulas no pequenas positivo para protemas de fusion ALK en otra realizacion mas, cancer positivo para los polinucleotidos de fusion EML4-ALK en otra realizacion mas, cancer de pulmon positivo para los polinucleotidos de fusion EML4-ALK en otra realizacion mas, cancer de pulmon de celulas no pequenas positivo para los polinucleotidos de fusion EML4-ALK en otra realizacion mas, cancer positivo para 15 protemas de fusion EML4-ALK en otra realizacion mas, cancer de pulmon positivo para protemas de fusion eML4- ALK en otra realizacion mas, o cancer de pulmon de celulas no pequenas positivo para protemas de fusion EML4- ALK en otra realizacion mas.The compound of formula (I) or a salt thereof has inhibitory activity against the kinase activity of the EML4-ALK fusion protein, in addition to growth inhibitory activity against cells dependent on the EML4-ALK fusion protein, and can used as an active ingredient in pharmaceutical compositions for preventing and / or treating cancer, such as lung cancer in one embodiment, non-small cell lung cancer or small cell lung cancer in another embodiment, positive cancer for ALK fusion polynucleotides in another embodiment, lung cancer positive for ALK fusion polynucleotides in another embodiment, non-small cell lung cancer positive for ALK fusion polynucleotides in yet another embodiment, cancer positive for ALK fusion proteins in another embodiment more, lung cancer positive for fusion proteins ALK in yet another embodiment, non-small cell lung cancer positive for fuser proteins ALK ion in yet another embodiment, positive cancer for EML4-ALK fusion polynucleotides in yet another embodiment, positive lung cancer for EML4-ALK fusion polynucleotides in yet another embodiment, non-small cell lung cancer positive for polynucleotides of EML4-ALK fusion in yet another embodiment, positive cancer for 15 EML4-ALK fusion proteins in yet another embodiment, positive lung cancer for eML4-ALK fusion proteins in yet another embodiment, or positive non-small cell lung cancer for EML4-ALK fusion proteins in yet another embodiment.

Claims (8)

55 1010 15fifteen 20twenty 2525 3030 3535 4040 45Four. Five 50fifty 1.- Un compuesto de formula (I) o una sal del mismo:1.- A compound of formula (I) or a salt thereof: R\ /X.^ /R2 N N H I,R \ /X.^ / R2 N N H I, RR (en la que los sfmbolos son como se definen a continuacion: -X-: un grupo de formula (II);(in which the symbols are as defined below: -X-: a group of formula (II); imagen1image 1 A: cloro, etilo o isopropilo; R1:A: chlorine, ethyl or isopropyl; R1: (1) fenilo en el que el carbono en la posicion 4 esta sustituido con -W-Y-Z y el carbono en la posicion 3 puede estar sustituido con un grupo seleccionado del grupo que consiste en halogeno, R00 y -O-R00;(1) phenyl in which the carbon in position 4 is substituted with -W-Y-Z and the carbon in position 3 may be substituted with a group selected from the group consisting of halogen, R00 and -O-R00; Z: un anillo heterodclico no aromatico que puede estar sustituido con uno o mas R00;Z: a non-aromatic heterodclic ring that may be substituted with one or more R00; R00: alquilo Ci-6 lineal o ramificada que puede estar sustituido con uno o mas halogenos;R00: linear or branched Ci-6 alkyl which may be substituted with one or more halogens; -W-: un enlace, piperidin-1,4-dnlo o piperazin-1,4-dnlo;-W-: a bond, piperidin-1,4-dnlo or piperazin-1,4-dnlo; -Y-: un enlace;-Y-: a link; R2:R2: (i) cicloalquilo que puede estar sustituido con uno o mas grupos seleccionados del grupo que consiste en N(alquilo Ci-6 lineal o ramificado)2, alquilo Ci-6 lineal o ramificado, -COO-alquilo Ci-6 lineal o ramificado, -OH, -COOH, -CONH-RZB y morfolinilo, o,(i) cycloalkyl which may be substituted with one or more groups selected from the group consisting of N (linear or branched Ci-6 alkyl) 2, linear or branched Ci-6 alkyl, -COO-linear or branched Ci-6 alkyl, -OH, -COOH, -CONH-RZB and morpholinyl, or, (ii) un anillo heterodclico no aromatico que puede estar sustituido con uno o mas grupos seleccionados del grupo que consiste en alquilo Ci-6 lineal o ramificado, -CO-alquilo Ci-6 lineal o ramificado, oxo, -CO-RZB y bencilo;(ii) a non-aromatic heterodclic ring which may be substituted with one or more groups selected from the group consisting of linear or branched Ci-6 alkyl, -CO-linear or branched Ci-6 alkyl, oxo, -CO-RZB and benzyl ; R : fenilo que puede estar sustituido con un grupo seleccionado del grupo que consiste en halogeno y -O-alquilo Ci-6 lineal o ramificado;R: phenyl which may be substituted with a group selected from the group consisting of halogen and linear or branched Ci-6 alkyl; R3 4: -H.R3 4: -H. 2. - El compuesto segun la reivindicacion i o una sal del mismo, en el que R1 es fenilo en el que el carbono en la posicion 4 esta sustituido con un grupo seleccionado del grupo que consiste en 4-(4-metilpiperazin-1-il)piperidin-1- ilo, 4-(1-metilpiperidin-4-il)piperazin-1-ilo, 4-metilpiperazin-1-ilo y 4-isopropilpiperazin-1-ilo, y el carbono en la posicion 3 puede estar sustituido con un grupo seleccionado del grupo que consiste en fluor, metilo, trifluorometilo y metoxi.2. - The compound according to claim io a salt thereof, wherein R1 is phenyl in which the carbon in position 4 is substituted with a group selected from the group consisting of 4- (4-methylpiperazin-1-yl ) piperidin-1- yl, 4- (1-methylpiperidin-4-yl) piperazin-1-yl, 4-methylpiperazin-1-yl and 4-isopropylpiperazin-1-yl, and carbon in position 3 may be substituted with a group selected from the group consisting of fluorine, methyl, trifluoromethyl and methoxy. 3. - El compuesto segun la reivindicacion 2 o una sal del mismo, en el que R2 es 4-hidroxiciclohexilo, 4-hidroxi-4- metilciclohexilo o tetrahidropiran-4-ilo.3. - The compound according to claim 2 or a salt thereof, wherein R2 is 4-hydroxycyclohexyl, 4-hydroxy-4- methylcyclohexyl or tetrahydropyran-4-yl. 4. - El compuesto segun la reivindicacion 1 o una sal del mismo, en el que dicho compuesto es:4. - The compound according to claim 1 or a salt thereof, wherein said compound is: 6-etil-5-[(trans-4-hidroxiciclohexil)amino]-3-{[4-(4-metilpiperazin-1-il)fenil]amino}pirazin-2-carboxamida,6-ethyl-5 - [(trans-4-hydroxycyclohexyl) amino] -3 - {[4- (4-methylpiperazin-1-yl) phenyl] amino} pyrazin-2-carboxamide, 6-etil-5-[(trans-4-hidroxiciclohexil)amino]-3-({4-[4-(4-metilpiperazin-1-il)piperidin-1-il]fenil}amino)pirazin-2-6-ethyl-5 - [(trans-4-hydroxycyclohexyl) amino] -3 - ({4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} amino) pyrazin-2- carboxamida,carboxamide, 5- [(trans-4-hidroxiciclohexil)amino]-6-isopropil-3- {[4-(4-metilpiperazin-1-il)fenil]amino}pirazin-2-carboxamida,5- [(trans-4-hydroxycyclohexyl) amino] -6-isopropyl-3- {[4- (4-methylpiperazin-1-yl) phenyl] amino} pyrazin-2-carboxamide, 6- etil-5-[(trans-4-hidroxiciclohexil)amino]-3-({4-[4-(4-metilpiperazin-1-il)piperidin-1-il]-3- (trifluorometil)fenil}amino)pirazin-2-carboxamida,6- ethyl-5 - [(trans-4-hydroxycyclohexyl) amino] -3 - ({4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] -3- (trifluoromethyl) phenyl} amino ) pyrazin-2-carboxamide, 6-etil-5-[(trans-4-hidroxiciclohexil)amino]-3-({3-metil-4-[4-(4-metilpiperazin-1-il)piperidin-1-il]fenil}amino)pirazin-2-6-ethyl-5 - [(trans-4-hydroxycyclohexyl) amino] -3 - ({3-methyl-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} amino) pyrazine -2- carboxamida,carboxamide, 5-[(trans-4-hidroxiciclohexil)amino]-6-isopropil-3-({4-[4-(4-metilpiperazin-1-il)piperidin-1-il]-3-5 - [(trans-4-hydroxycyclohexyl) amino] -6-isopropyl-3 - ({4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] -3- (trifluorometil)fenil}amino)pirazin-2-carboxamida,(trifluoromethyl) phenyl} amino) pyrazin-2-carboxamide, 55 1010 15fifteen 20twenty 2525 3030 3535 6-etil-5-[(cis-4-hidroxi-4-metilciclohexil)amino]-3-({3-metil-4-[4-(4-metilpiperazin-1-il)piperidin-1-il]fenil}amino)pirazin-2-6-ethyl-5 - [(cis-4-hydroxy-4-methylcyclohexyl) amino] -3 - ({3-methyl-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl } amino) pyrazin-2- carboxamida,carboxamide, 6-etil-5-[(trans-4-hidroxicidohexil)amino]-3-{[4-(4-isopropilpiperazin-1-il)-3-metilfenil]amino}pirazin-2-carboxamida,6-ethyl-5 - [(trans-4-hydroxycidohexyl) amino] -3 - {[4- (4-isopropylpiperazin-1-yl) -3-methylphenyl] amino} pyrazin-2-carboxamide, 6-etil-5-[(trans-4-hidroxi-4-metilcidohexil)amino]-3-({3-metil-4-[4-(4-metilpiperazin-1-il)piperidin-1-6-ethyl-5 - [(trans-4-hydroxy-4-methylcidohexyl) amino] -3 - ({3-methyl-4- [4- (4-methylpiperazin-1-yl) piperidin-1- il]fenil}amino)pirazin-2-carboxamida,il] phenyl} amino) pyrazin-2-carboxamide, 6-etil-3-({3-metil-4-[4-(4-metilpiperazin-1-il)piperidin-1-il]fenil}amino)-5-(tetrahidro-2H-piran-4-ilamino)pirazin-2-6-ethyl-3 - ({3-methyl-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} amino) -5- (tetrahydro-2H-pyran-4-ylamino) pyrazin-2- carboxamida,carboxamide, 6-cloro-5-[(trans-4-hidroxiciclohexil)amino]-3-({3-metil-4-[4-(4-metilpiperazin-1-il)piperidin-1-il]fenil}amino)pirazin-2-6-chloro-5 - [(trans-4-hydroxycyclohexyl) amino] -3 - ({3-methyl-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} amino) pyrazine -2- carboxamida,carboxamide, 6-etil-3-({4-[4-(4-metilpiperazin-1-il)piperidin-1-il]fenil}amino)-5-(tetrahidro-2H-piran-4-ilamino)pirazin-2-carboxamida,6-ethyl-3 - ({4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} amino) -5- (tetrahydro-2H-piran-4-ylamino) pyrazin-2- carboxamide, 6-etil-3-({3-metoxi-4-[4-(4-metilpiperazin-1-il)piperidin-1-il]fenil}amino)-5-(tetrahidro-2H-piran-4-ilamino)pirazin-2-6-ethyl-3 - ({3-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} amino) -5- (tetrahydro-2H-pyran-4-ylamino) pyrazin-2- carboxamida,carboxamide, 6-isopropil-3-({4-[4-(4-metilpiperazin-1-il)piperidin-1-il]fenil}amino)-5-(tetrahidro-2H-piran-4-ilamino)pirazin-2-6-Isopropyl-3 - ({4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} amino) -5- (tetrahydro-2H-pyran-4-ylamino) pyrazin-2- carboxamida,carboxamide, 6-etil-3-{[3-fluoro-4-(4-metilpiperazin-1-il)fenil]amino}-5-(tetrahidro-2H-piran-4-ilamino)pirazin-2-carboxamida, 6-isopropil-3-{[3-metoxi-4-(4-metilpiperazin-1-il)fenil]amino}-5-(tetrahidro-2H-piran-4-ilamino)pirazin-2-carboxamida, 6-isopropil-3-{[4-(4-metilpiperazin-1-il)fenil]amino}-5-(tetrahidro-2H-piran-4-ilamino)pirazin-2-carboxamida, o 6-etil-3-({3-metil-4-[4-(1-metilpiperidin-4-il)piperazin-1-il]fenil}amino)-5-(tetrahidro-2H-piran-4-ilamino)pirazin-2- carboxamida.6-ethyl-3 - {[3-fluoro-4- (4-methylpiperazin-1-yl) phenyl] amino} -5- (tetrahydro-2H-pyran-4-ylamino) pyrazin-2-carboxamide, 6-isopropyl -3 - {[3-methoxy-4- (4-methylpiperazin-1-yl) phenyl] amino} -5- (tetrahydro-2H-pyran-4-ylamino) pyrazin-2-carboxamide, 6-isopropyl-3- {[4- (4-methylpiperazin-1-yl) phenyl] amino} -5- (tetrahydro-2H-pyran-4-ylamino) pyrazin-2-carboxamide, or 6-ethyl-3 - ({3-methyl- 4- [4- (1-methylpiperidin-4-yl) piperazin-1-yl] phenyl} amino) -5- (tetrahydro-2H-pyran-4-ylamino) pyrazine-2-carboxamide. 5. - Una composicion farmaceutica, que comprende el compuesto segun la reivindicacion 1 o una sal del mismo y un excipiente farmaceuticamente aceptable.5. - A pharmaceutical composition, comprising the compound according to claim 1 or a salt thereof and a pharmaceutically acceptable excipient. 6. - Compuesto segun la reivindicacion 1 o una sal del mismo para su uso en un metodo para inhibir la actividad de cinasa de la protema de fusion EML4-ALK.6. - Compound according to claim 1 or a salt thereof for use in a method to inhibit the kinase activity of the EML4-ALK fusion protein. 7. - Una composicion farmaceutica para su uso en un metodo de prevencion o tratamiento de cancer, cancer de pulmon, cancer de pulmon de celulas no pequenas, cancer de pulmon de celulas pequenas, cancer positivo para los polinucleotidos de fusion EML4-ALK, cancer de pulmon positivo para los polinucleotidos de fusion EML4-ALK, o cancer de pulmon de celulas no pequenas positivo para los polinucleotidos de fusion EML4-ALK, que comprende el compuesto segun la reivindicacion 1 o una sal del mismo.7. - A pharmaceutical composition for use in a method of prevention or treatment of cancer, lung cancer, non-small cell lung cancer, small cell lung cancer, EML4-ALK fusion polynucleotide positive cancer, cancer of lung positive for EML4-ALK fusion polynucleotides, or non-small cell lung cancer positive for EML4-ALK fusion polynucleotides, comprising the compound according to claim 1 or a salt thereof. 8. - Compuesto segun la reivindicacion 1 o una sal del mismo para su uso en un metodo de prevencion o tratamiento de cancer, cancer de pulmon, cancer de pulmon de celulas no pequenas, cancer de pulmon de celulas pequenas, cancer positivo para los polinucleotidos de fusion EML4-ALK, cancer de pulmon positivo para los polinucleotidos de fusion EML4-ALK, o cancer de pulmon de celulas no pequenas positivo para los polinucleotidos de fusion EML4- ALK.8. - Compound according to claim 1 or a salt thereof for use in a method of prevention or treatment of cancer, lung cancer, non-small cell lung cancer, small cell lung cancer, polynucleotide positive cancer of EML4-ALK fusion, lung cancer positive for EML4-ALK fusion polynucleotides, or non-small cell lung cancer positive for EML4-ALK fusion polynucleotides.
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